Drug vehicle compositions and methods of use thereof

ABSTRACT

The invention is directed to topical drug vehicle platform compositions for ophthalmological and dermatological use. These compositions comprise a means to sequester tears and an ophthalmological drug. The invention is further directed to methods of treating a spectrum of ocular surface disease epitheliopathies including but not limited to dry eye in a human or mammal. The invention is further directed to contact lenses, punctum plugs, pellets or any other device used to deliver drugs to the surface of the eye, coated or infused with compositions of the invention.

FIELD OF THE INVENTION

The invention is directed to topical drug vehicle platform compositionsfor ophthalmological and dermatological use. These compositions comprisea means to sequester tears and an ophthalmological drug. The inventionis further directed to methods of treating a spectrum of ocular surfacedisease epitheliopathies including but not limited to dry eye in a humanor mammal. The invention is further directed to contact lenses, punctumplugs, pellets or any other device used to deliver drugs to the surfaceof the eye, coated or infused with compositions of the invention.

BACKGROUND OF THE INVENTION

Artificial Tears

The eye produces tears that are spread across the eye while blinking.The unique components of tears combined with the blinking process createa tear film that is made up of a mucous layer, an aqueous layer and alipid layer. This tear film undergoes significant forces that cancompromise the integrity of the film including: 1) evaporation, 2)spreading along the ocular surface, which is driven by high shearblinks, 3) draining, which is aided by blink powered lacrimal pumpingand 4) low shear flow along the lid tear menisci. To maintain the tearfilm the film is continually replenished with new tear film componentsupon each blink, which is triggered by tear breakup and corneal surfacenerve excitation. This unique system creates a barrier between theenvironment and the surface of the eye and removes any irritants thatmay enter the eye. Further, tears have critical components derived fromthe blood plasma that are filtered to nourish the ocular surface, reduceinfection risk and promote healing of ocular surface tissues. A healthytear film is necessary for optimal vision just as an unhealthy tear filmresults in degradation of visual quality and or acuity. There areseveral events that can cause a reduction in the quantity or quality oftears including intra- or extraocular surgery affecting the ocularsurface, dry eye syndrome, dry eye following eye surgery, ocular surfaceabnormalities from medication and or preservative toxicity, and contactlens solution and or contact lens use.

The tear film is the single most important optical surface. Disturbancesthat affect the quality and duration of that film on the cornea candramatically alter quality of vision. These disturbances include reducedvolume as measured by Schirmer's test, reduced tear breakup time andreduced tear prism (i.e. the measure of the meniscus along the lower lidwhere tears flow). Unfortunately, the true measures of a healthy tearfilm: the thickness and or volume of each layer, the composition withineach layer, and the resulting flow properties and stabilization of thetear film are not easily measured. Tear abnormalities manifest as alarge range of tear deficiencies from composition abnormalities of oneor more of the mucous, aqueous and lipid layers to volume abnormalitiesincluding reduction in the thickness and or volume of one or more ofthese layers and combinations thereof.

Dry eye is a generic term for any abnormality in tear layer thickness ortear layer composition. Dry eye is a common affliction that is caused bythe failure of the eye to produce either an adequate amount or maintaina proper balance of tear components in the mucous, aqueous or lipidlayers. In either instance, the tear film that normally covers the eyebecomes unstable (i.e. no longer covers the entire eye evenly and for asufficient period.) A sufficient period is typically about eightseconds. Tear film instability causes tears to bead up leaving surfacecoverage dry spots while failing to remove irritants. These dry spotsand irritants cause many of the conditions associated with dry eye suchas burning, stinging, itching and tired eyes. Dry eye symptoms can beexacerbated by activities that extend the time between eye blinks suchas prolonged computer use and reading. Even mild tear film degradationcan reduce the tear break up time (“TBUT”) leading to excessiveblinking. Blinking may achieve brief moments of complete even tear filmcoverage where vision is optimized. However, this relief is sporadic andshort-lived, and the tear film may become degraded altogether makingeven frequent blinking ineffective.

Dry eye often occurs following any incisional or ablative procedure thatcuts corneal nerves, by reducing the neurologic trigger for tearsecretion, or disrupting the external surface creating abnormalspreading and elevated dry spots (dellen). Procedures include: cornealor scleral eye surgery including but not limited to cataract incisions;corneal transplant surgery; glaucoma surgery filtering blebs; and anyincisional or ablative corneal surgery. Dry eye following eye surgerycan lead to increased pain to the patient, increased infection risk,reduced vision and increased sensitivity to topical medications andpreservatives. This increased sensitivity may exacerbate ocular surfacedisease, have similar symptomatology to dry eye, and result in prolongedepithelial healing times.

Current artificial tear compositions designed to reduce or alleviate dryeye contain polymers that act to mimic the mucous, aqueous and or lipidlayers of the tear film to maintain the stability of the film andprevent rapid evaporation. High viscosity artificial tear compositionsmaintain a longer lasting tear film. However, these compositions causeviscous drag on the eye lids while blinking creating an uncomfortable“sticky” sensation, may be difficult to apply and create crust on theeye lids. These high viscosity compositions also result in blurredvision, typically for several minutes or longer. Low viscositycompositions do not maintain a long-lasting tear film, in part, due to aquicker loss of these aqueous solutions to evaporation and drainingaided by blink powered lacrimal pumping.

Current artificial tear compositions for treating dry eye are deficientfor many reasons including: i) they maintain a stable tear film for onlya short period of time, typically 15 minutes or less after which tearproperties return to baseline; ii) higher viscosity formulations onlylast modestly longer (about 25 minutes or less) and they cause blurredvision for a relatively long period of time (as long as 12 minutes forRefresh® Celluvisc (400 cps), frequently requiring frantic blinkinguntil it thins out enough and stabilizes; iii) they either do notprovide an evaporative shield to reduce drying or they have a syntheticand or oily feeling from added lipids or lipid-like substances that donot stabilize the aqueous layer; iv) they do not provide a protectivecoating over the conjunctiva of the lids and or sufficiently dissolvelipid inspissation within Meibomian glands, both hallmarks of dry eyecharacterized by such Meibomian gland inspissation and dysfunction(“MGD”); v) they do not provide a physiologically enhanced environmentfor epithelial cell healing and maintain integrity; vi) they do notprevent, reduce, or help dissolve protein, cholesterol, or dried mucousthat may deposit on contact lens surfaces, the corneal epithelium, orthe conjunctiva of the lid and irritate or otherwise degrade these cellmembranes; vii) they do not significantly promote tear secretion orprovide prolonged exposure to and retention of existing tears(prescription drugs such as Restasis® or Xiidra® attempt to increasetear secretion but cause only marginal increases); and viii) they resultin higher osmolality and wetting angle making tear spread more difficultand uneven.

Efforts to create evaporative shielding to retain the aqueous tearlayer, such as addition of lipids or phospholipids are compromised notonly by the synthetic oily unnatural sensation that results, but also bythe poor aqueous layer stabilization and very short duration of theinstilled drop or prolonged blur of a more viscous slightly longerlasting artificial tear. While the goal is retention of the artificialtear in the cul de sac, which allows each blink to pull more of theartificial tear across the cornea, there is tremendous lacrimal ductdrainage via capillary attraction limiting this benefit withconventional tear formulations. The longest lasting artificial tears onthe market use high concentrations of viscosity enhancing agents.Celluvisc® (Celluvisc is a registered trademark of Allergan, Inc.),which uses high viscosity carboxymethyl cellulose (“CMC”) 1%-about 350centipoise (“cps”) viscosity, and Refresh Liquigel® (Refresh Liquigel isa registered trademark of Allergan, Inc.), which uses a blend of 0.35%high viscosity CMC and 0.65% low viscosity CMC—about 70 cps, are twosuch compositions. These high viscosity artificial tear compositions arelong lasting but cause significantly blurred vision lasting up to 10minutes or longer.

Artificial tear compositions have made progress. This progression hasbeen based on improving difficult to measure TBUT, duration of addedwetting, and degree and duration of blur relative to viscosity. Thefirst generation of artificial tears was a simple saline solution withthe addition of other electrolytes and certain minerals still found ineye drops today, such as Theratears® (Theratears is a registeredtrademark of Advanced Vision Research, Inc.). A second generation wasdeveloped by adding natural and synthetic polymers, particularlypolyvinyl alcohols and cellulose derivative viscosity agents. The mostnatural feeling and therefore popular formulation from the secondgeneration is Refresh® tears (Refresh is a registered trademark ofAllergan Pharmaceuticals, Inc.). A third generation was developed byadding hyaluronic acid (hyaluronates). The third generation promotesslower lacrimal duct drainage and greater retention on the eye byproviding non-Newtonian flow properties. However, the third generationhas only moderate tear layer stabilization and retention. The thirdgeneration also decreases the duration of blur and stabilizes the tearfilm. However, third generation formulations are oilier and theirunnatural, ‘moisture-lacking’ sensation makes them less popular thanmany products on the market today from the second generation. Further,the third generation has very little demonstrated therapeutic clinicaldifferentiation from the second generation. A fourth generation wasdeveloped consisting of lipid-based oil—in—water (“O/W”) emulsions. TheO/W emulsions of the fourth generation reduces tear film evaporation,stabilizes the lipid layer and prolongs duration. These formulationsrequire the addition of nonionic or cationic surfactants forstabilization. However, these formulations do not promote increasedspreading, provide any useful adjunctive aqueous layer stabilizersacross the eye, or retard high shear blink lacrimal pumping leading tominimally enhanced retention. These formulations may be limited by thelow concentrations of surfactants in conventional artificial tears dueto their known toxicity at 1.0% or greater. Additionally, as with thethird generation, the fourth-generation artificial tear has minimaltherapeutic detectable clinical benefit and a synthetic and lesscomfortable quality.

Drug Vehicles

Ophthalmic drug efficacy is severely limited by non-compliance.Compliance is adversely affected by the reduced comfort, irritation, andtransient quality of vision loss, which lasts minutes to tens ofminutes, that is common to many drugs. In particular, these adverseeffects are caused by suspensions commonly used for highly lipophilicdrugs or the requirement of very high topical concentrations for highlyhydrophilic drugs.

The fundamental challenges of ophthalmic delivery vehicles are toimprove comfort; minimize visual blur on instillation; increase drugsolubility; increase drug residence time and permeation through thecornea to achieve greater intraocular delivery; reduce systemic drugabsorption; and cause minimal local adverse effect. Unfortunately, theseobjectives are not met by current ophthalmic formulations.

Current artificial tear vehicles may be used for drug solubilization,but do not confer increased drug residence time or offer other efficacybenefits. More viscous artificial tears use high concentrations ofviscosity enhancing agents, such as Celluvisc® (Celluvisc is aregistered trademark of Allergan, Inc.), high viscosity carboxymethylcellulose (CMC) 1%-about 350 centipoise (cps) viscosity, and RefreshLiquigel® (Refresh Liquigel is a registered trademark of Allergan,Inc.), a blend of 0.35% high viscosity CMC and 0.65% low viscosityCMC-about 70 cps, but these formulations have prolonged visual blur thatmay last for 10 minutes or longer, greatly reducing compliance. Theseartificial tear vehicles also do not leach drug slowly but ratherrelease a lot to drainage.

Gelling agents have been used with some success in increasing drugresidence time and improving drug solubility. By definition such agentsare instilled as liquid and then almost immediately triggered to a gelphase, where drug residence time is increased and drug release timeextended. Timoptic XE® gel (gellan gum; Timoptic XE is a registeredtrademark of Merck & Co, Inc.), AzaSite® (Azasite is a registeredtrademark of Insite Vision, Inc.) (polycarbophil, poloxamer), andBesivance® (Besivance is a registered trademark of Bausch & Lomb, Inc.),(polycarbophil, poloxamer), 0.3% alginate Keltrol®) (Keltrol is aregistered trademark of CP Kelco U.S., Inc.) are examples of suchagents, where polycarbophil-poloxamer gels are commercially known asDurasite® (Durasite is a registered trademark of Insite Vision, Inc.).

However, most gelling agents: 1) increase blur on instillation; 2) causelid and lash encrusted gel residue; 3) cause irritation/stinging oninstillation; and 4) allow substantial active drug to be releasedsystemically and may have systemic side effects. For drugs with minimalsystemic side effects, or intended for only acute use of a few days,these issues are somewhat mitigated; but for drugs with higher systemiceffect profiles, particularly lipophilic drugs, and more particularly aschronic use drugs, these issues can seriously affect compliance.

Gelling agents experience a phase transition to a highly viscous state,typically achieving 500-1000 cps or more after their transition. Ionic,pH, and thermal triggers are typically used. However, the high shearforce of each blink breaks up such phase modified films into discreteparticles easily drained into the nasolacrimal duct to the nasalturbinates where residual drug may readily enter systemic circulation.Many gelling agents combine poloxamers of various molecular weights withviscosity enhancers or other gelling agents to create the desired phasetransition from liquid on instillation to gel. Typically for thoseformulations using poloxamer without a second gelling agent, poloxamerconcentrations of 15% or greater are needed to achieve gel-transitiontemperatures at body temperature (37° C.).

Patel (Int. J. of Pharm. Chem. Sci., Vol. 1, October-December 2012)describes the use of poloxamer and a viscosity enhancing agent—a lowmolecular weight, low viscosity hydroxypropylmethyl cellulose (HPMCE50LV) 1.5% with brimonidine and demonstrates on testing concentrationsof poloxamer with the HPMC from 1% to 19%, no clinically useful gellingcapacity in vitro below 15%. Given the dilution of tear film, thistypically requires about 21% poloxamer to achieve phase transition togel on ophthalmic instillation. For example, Qian (Drug Dev. AndIndustrial Pharmacy, 2010, 36(1): 1340-1347) describes an in-situgelling system for methazolamide, a carbonic anhydrase inhibitor(glaucoma), using 21% poloxamer 407 and 10% poloxamer 188 to achieve apreferred phase transition to gel. High viscosity gels have beendescribed with similar limitations to in situ gels, specifically tradingoff the most egregious noncompliance factors of lid and lash residue andviscous lid drag for lesser amounts of both and with less but stillsubstantially prolonged vision blur.

Use of low viscosity agents reverses the predicament. Other compositionsattempt to optimize compliance with formulations that have low viscosityagents such that comfort is good, vision is good and surface residue isabsent. However, in such formulations, tear dilution is almostimmediate, and drug residence time is severely limited versus in situgels or viscous liquid gels. Therefore, formulations either improvecompliance or enhance efficacy but not both. This is often seen withvehicles for dry eye. Refresh Liquigel® at 70 cps and Celluvisc® at 300cps are such examples where vision blur is noted.

Thus, there is a need in the art for a topical drug vehicle that canmaintain a drug on the surface of the eye or skin. This vehicle shouldbe comfortable to the user and increase residency time, absorbency,safety or efficacy of the drug on the surface of the eye or skin.

SUMMARY OF THE INVENTION

Artificial Tears

In certain embodiments, the present invention is directed to artificialtear compositions comprising a means for inducing tears and a means forsequestering tears.

In a preferred embodiment, the means for inducing tears is selected froma pH from about 5 to about 6, a terpenoid and an osmolarity of fromabout 350 to about 550 milliosmoles.

In another preferred embodiment, the means for sequestering tearscomprises from about 1.5% to about 5.9% w/v total volume of one or morenonionic surfactants and one or more viscosity enhancers, wherein theone or more viscosity enhancers provides a viscosity of from about 50 toabout 10,000 centipoise at 0 shear to 1 second.

In more preferred embodiment, the one or more nonionic surfactants areselected from the group consisting of polysorbates, poloxamers, polyoxylcastor oils, cyclodextrins (alpha, beta or gamma) and combinationsthereof.

In another more preferred embodiment, the one or more viscosityenhancers are selected from the group consisting of cellulosederivatives, carbomers, gums, and hyaluronic acids, dextrans, polyvinylalcohol, polyacrylic acids, povidone, polyethylene glycols, propyleneglycol, chitosans and combinations thereof, even more preferably the oneor more viscosity enhancers are selected from the group consisting ofcellulose derivatives, carbomers, polyvinyl alcohol, polyethyleneglycols and combinations thereof.

In another embodiment, the artificial tear compositions of the presentinvention further comprise a polyol, preferably selected from the groupconsisting of mannitol, xylitol, sorbitol, isosorbide, erythritol,glycerol, maltitol and a combination thereof.

In another embodiment, the artificial tear compositions of the presentinvention further comprise one or more electrolytes, preferably selectedfrom the group consisting of magnesium ions, sodium chloride, potassiumchloride and a combination thereof.

In another embodiment, the artificial tear compositions of the presentinvention further comprise one or more lipids, preferably omega 3 fattyacids.

In another preferred embodiment, the present invention is directed toartificial tear compositions comprising one or more nonionicsurfactants, preferably at a concentration from about 1.25% to about10.0% w/v, one or more viscosity enhancers and a means of inducingtearing including via nociception, preferably selected from the groupconsisting of a pH below 6.0; an osmolarity of about 250 mosm less, anosmolarity of 350 mosm or more; an osmolarity of 400 mosm or more; anosmolarity of 450 mosm or more; from about 0.05 to about 4.0 mM mentholand a combination thereof, preferably resulting in induced tearing andprolonged sequestration.

In another preferred embodiment, the present invention is directed toartificial tear compositions comprising from about 1.5% to about 5.9%w/v total concentration of one or more nonionic surfactants, one or moreviscosity enhancers, a means of inducing tearing selected from the groupconsisting of a pH below 6.0; an osmolarity of 350 mosm or more;menthol, and a combination thereof.

In another preferred embodiment, the present invention is directed toartificial tear compositions comprising at least 1.0% w/v totalconcentration of one or more nonionic surfactants, preferably from about1.0% to about 10.0% w/v, more preferably from about 1.5% to about 5.9%w/v one or more viscosity enhancers and menthol.

In another preferred embodiment, the present invention is directed toartificial tear compositions comprising:

-   -   one or more nonionic surfactants selected from the group        consisting of poloxamers, polysorbates, cyclodextrins, alkylaryl        polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and        polyoxyls at a total concentration from about 1.25% to about        7.0% w/v, preferably selected from the group consisting of about        0.01% to about 4.0% w/v of a polysorbate, from about 0.01% to        about 3.0% w/v of one or more poloxamers, from about 0.01% to        about 1.0% w/v of a polyoxyl and from about 0.01% to about 5.0%        w/v hydroxypropyl-gamma-cyclodextrin;    -   a viscosity enhancer selected from the group consisting of        cellulose derivatives, carbomers, gums, dextrans, polyvinyl        alcohol, polyacrylic acids, povidone, polyethylene glycol,        propylene glycol, chitosans, hyaluronates, hyaluronic acids and        combinations thereof; from about 0.01% to about 3.0% w/v of an        electrolyte selected from the group consisting of sodium        chloride, potassium chloride, magnesium ions and combinations        thereof, preferably the electrolyte is selected from about 0.01%        to about 0.25% w/v magnesium ions, from about 0.10% to about        2.0% w/v sodium chloride, from about 0.1% to about 0.5% w/v        potassium chloride and combinations thereof;    -   a means of inducing tearing selected from the group consisting        of a pH below 6.0; an osmolarity of 350 mosm or more; menthol,        and a combination thereof; and optionally, about 0.1% w/v        sorbate,        preferably, wherein the concentration of the viscosity enhancer        provides a composition with a viscosity from about 0.1 to about        1,000 centipoise (cps), and preferably, wherein a low shear        viscosity is from about 1 to about 1000 cps and a final high        shear viscosity is about 30 cps or less.

In another preferred embodiment, the present invention is directed toartificial tear compositions comprising:

-   -   one or more nonionic surfactants selected from the group        consisting of poloxamers, polysorbates, cyclodextrins, alkylaryl        polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and        polyoxyls at a total concentration from about 1.25% to about        7.0% w/v, preferably the one or more nonionic surfactants are        selected from the group consisting of from about 0.01% to about        4.0% w/v of a polysorbate, from about 0.01% to about 3.0% w/v of        one or more poloxamers, from about 0.01% to about 1.0% w/v of a        polyoxyl and optionally, from about 0.01% to about 5.0% w/v        hydroxypropyl-gamma-cyclodextrin; optionally, from about 0.1% to        about 0.75% w/v sodium chloride;    -   from about 0.01 mM to about 0.50 mM menthol;    -   optionally, from about 0.1% to about 4% w/v of a polyol,        preferably the polyol is mannitol or glycerol at a concentration        from about 1.0% to about 2.5% w/v;    -   a viscosity agent selected from the group consisting of        cellulose derivatives, carbomers, gums, dextrans, polyvinyl        alcohol, polyacrylic acids, povidone, polyethylene glycol,        propylene glycol, chitosans, hyaluronates, hyaluronic acids and        combinations thereof, preferably wherein the composition has a        viscosity from about 1 to about 1,000 centipoise; and    -   optionally, from about 0.01% to about 0.25% w/v magnesium ions.

In a preferred embodiment, the present invention is directed toartificial tear compositions comprising:

-   -   from about 2.0% to about 4.0% w/v of one or more nonionic        surfactants selected from the group consisting of polysorbates,        poloxamers, polyoxyl castor oils and combinations thereof;    -   from about 0.5% to about 2.0% w/v of a viscosity enhancer        selected from the group consisting of carboxymethyl cellulose        and carbomer 940;    -   from about 1.0% to about 5.0% w/v mannitol;    -   from about 0.5% to about 1.0% w/v of a polyethylene glycol        selected from polyethylene glycol 400, polyethylene glycol 6000,        polyethylene glycol 10000, polyethylene glycol 20000 and a        combination thereof;    -   from about 0.1% to about 2.0% w/v sodium chloride;    -   from about 0.1% to about 0.12% w/v sorbate;    -   from about 3.0 to about 10.0 millimolar citrate buffer,    -   wherein w/v denotes weight by total volume of the composition        and wherein the composition has a pH from about 5.0 to about        7.4, preferably from about 5.0 to about 6.0.

In another preferred embodiment, the present invention is furtherdirected to methods of treating dry eye comprising administering acomposition of the present invention to a subject in need thereof.

In another preferred embodiment, the present invention is furtherdirected to methods of treating ocular surface defects, deficiencies anddisease selected from the group consisting of superficial punctatekeratitis, epithelial abrasions, post-surgical ocular surfaceabnormality such as post glaucoma shunt, post cataract, post refractivesurgery, dry eye syndrome, keratoconjunctivitis sicca, dry eye followingincisional or ablative surgery such as corneal/glaucoma surgery,cataract incisions, corneal transplant, glaucoma surgery filteringblebs, ocular surface abnormalities caused by medication, preservatives,contact lens solution and contact lens use or methods of treatingendophthalmitis.

In another preferred embodiment, the present invention is furtherdirected to methods of treating eye pain comprising administering acomposition of the present invention to a subject in need thereof.

In another preferred embodiment, the present invention is furtherdirected to methods of enhancing wound healing following corneal surgerycomprising administering a composition of the present invention to asubject in need thereof.

In another preferred embodiment, the present invention is furtherdirected to methods of treating Meibomian gland dysfunction comprisingadministering a composition of the present invention to a subject inneed thereof.

In another preferred embodiment, the present invention is furtherdirected to an artificial tear composition comprising one or morenonionic surfactants, one or more viscosity enhancers, a polyol, one ormore electrolytes and menthol.

In another preferred embodiment, the one or more nonionic surfactantsare polysorbate 80, poloxamer 407, poloxamer 188 and polyoxyl castoroil.

In another preferred embodiment, the one or more viscosity enhancers areselected from cellulose derivatives.

In another preferred embodiment, the polyol is mannitol.

In another preferred embodiment, the one or more electrolytes aremagnesium chloride and sodium chloride.

In another preferred embodiment, the one or more nonionic surfactantsare polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oiland hydroxypropyl-gamma-cyclodextrin.

In another preferred embodiment, the artificial tear compositions of thepresent invention further comprise a polyethylene glycol.

In another preferred embodiment, the polyethylene glycol is polyethyleneglycol 400.

In another preferred embodiment, the artificial tear compositions of thepresent invention further comprise ascorbic acid or d-alpha tocopherol.

In another preferred embodiment, the artificial tear compositions of thepresent invention further comprise sorbate.

In another preferred embodiment, the total concentration of the one ormore nonionic surfactants is at least 1.0% w/v, preferably from about1.0% w/v to about 10.0% w/v and more preferably from about 1.5% w/v toabout 5.9% w/v.

In another preferred embodiment, the cellulose derivative is at aconcentration that provides a viscosity equivalent tohydroxypropylmethyl cellulose at a concentration from about 0.01% toabout 2.5% w/v, more preferably from about 0.01% to about 1.5% w/v orhigh molecular weight carboxymethyl cellulose at a concentration fromabout 0.01% to about 1.5% w/v, wherein “high molecular weight” is at3,500 cps or more.

In another preferred embodiment, the menthol is at a concentration fromabout 0.01 to about 4.0 millimolar, more preferably from about 0.01 toabout 0.40 millimolar or from about 0.2 to about 2.5 millimolar or fromabout 0.2 to about 1.6 millimolar.

In another preferred embodiment, the present invention is furtherdirected to an artificial tear composition comprising from about 0.5% toabout 1.5% w/v polysorbate 80, preferably, from about 1.00% to about1.50% w/v polysorbate 80, from about 0.5% to about 1.5% w/v poloxamer407, preferably from about 0.7% to about 1.00% w/v poloxamer 407, fromabout 0.20% to about 1.00% w/v poloxamer 188, from about 0.01% to about0.50% w/v polyoxyl castor oil, preferably from about 0.01% to about0.30% w/v polyoxyl castor oil, from about 0.1% to about 2.0% w/vcarboxymethyl cellulose, preferably from about 0.1% to about 1.5% w/vcarboxymethyl cellulose and from about 0.01 to about 0.50 millimolarmenthol, preferably from about 0.01 to about 0.40 millimolar menthol andoptionally, from about 0.1% about 1.5% w/v polyethylene glycol 400,preferably about 0.50% w/v polyethylene glycol 400, from about 0.5% toabout 1.5% mannitol, preferably about 0.75% or about 1.00% w/v mannitol,about 0.10% w/v magnesium chloride, about 0.35% to about 0.45% w/vsodium chloride and from about 3 to about 4 millimolar of a bufferselected from phosphate and citrate.

In another preferred embodiment, the artificial tear compositions of thepresent invention further comprise from about 0.1% to about 0.15% w/vsorbate, preferably from about 0.11% to about 0.12% w/v sorbate.

In another preferred embodiment, the artificial tear compositions of thepresent invention further comprise greater than 0.1% w/v sorbate,preferably from 0.11% to about 10.0% w/v.

In another preferred embodiment, the artificial tear compositions of thepresent invention further comprise from about 0.25% to about 5.5% w/vhydroxypropyl-gamma-cyclodextrin, preferably from about 1.5% to about2.0% w/v.

In another preferred embodiment, the artificial tear compositions of thepresent invention further comprise from about 1 to about 200international units of d-alpha tocopherol, preferably from about 30 toabout 50 international units.

In another preferred embodiment, the artificial tear compositions of thepresent invention have a pH from about 5.7 to about 8.0, preferably fromabout 5.7 to about 6.5.

In another preferred embodiment, the present invention is furtherdirected to an artificial tear composition comprising from about 0.5% toabout 1.5% w/v polysorbate 80, preferably, from about 1.00% to about1.50% w/v polysorbate 80, from about 0.5% to about 1.5% w/v poloxamer407, preferably from about 0.7% to about 1.00% w/v poloxamer 407, fromabout 0.20% to about 1.00% w/v poloxamer 188, from about 0.01% to about0.50% w/v polyoxyl castor oil, preferably from about 0.01% to about0.30% w/v polyoxyl castor oil, from about 0.1% to about 2.0% w/vhydroxypropylmethyl cellulose, preferably from about 0.1% to about 1.2%w/v hydroxypropylmethyl cellulose, from about 0.1% about 1.5% w/vpolyethylene glycol 400, preferably about 0.50% w/v polyethylene glycol400, from about 0.5% to about 1.5% mannitol, preferably about 0.75% orabout 1.00% w/v mannitol, about 0.10% w/v magnesium chloride and about0.35% to about 0.45% sodium chloride, from about 0.1% to about 0.11% w/vsorbate, from about 1.5% to about 2.5% w/vhydroxypropyl-gamma-cyclodextrin, from about 10 to about 200international units of d-alpha tocopherol and wherein the compositionhas a pH from about 5.7 to about 8.0.

Drug Vehicles

In one embodiment, all artificial tear compositions of the presentinvention are capable of being used as drug vehicles.

In another preferred embodiment, the present invention is directed to anophthalmological drug composition comprising a means to sequester tearsand an ophthalmological drug, preferably selected from the groupconsisting of trehalose, cyclosporine (cyclosporine is the activeingredient in Restasis® available from and a registered trademark ofAllergan, Inc. and Cequa® available from and a registered trademark ofSun Pharma Global FZE), lifitegrast (lifitegrast is the activeingredient in Xiidra® available from and a registered trademark ofSARcode Bioscience Inc.), diquafosol (diquafosol is the activeingredient in Diquas® available from and a registered trademark ofSanten Pharmaceutical Co., Ltd), a C-terminal 25 amino acid fragment oflacritin (known as Lacripep® available from and a registered trademarkof TearSolutions, LLC), lacritin, KPI-121 (KPI-121 is the activeingredient in Inveltys™ available from Kala Pharmaceuticals),tivanisiran (tivanisiran is the active ingredient in Sylentis® availablefrom and a registered trademark of Sylentis, S.A.U.), omega 3 fattyacids, an antibiotic, a steroid anti-inflammatory, a nonsteroidalanti-inflammatory, a glaucoma drug, a prostaglandin, a muscarinicreceptor agonist, a miotic agent, drugs known to cause dry eye such astopical antihistamines and alpha 2 agonists (brimonidine), and acombination thereof.

In another preferred embodiment, the present invention is furtherdirected to an ophthalmological drug vehicle composition comprising anophthalmological drug and one or more nonionic surfactants and at leastone excipient selected from a viscosity enhancer, a polyol and anelectrolyte, preferably the ophthalmological drug is selected from thegroup consisting of diquafosol, cyclosporine, a prostaglandin, anantibiotic, a muscarinic receptor agonist, a non-steroidalanti-inflammatory, a steroidal anti-inflammatory, GLC acetylsalicylicacid, salicylic acid and a combination thereof.

In another embodiment, the compositions of the present invention arecapable of solubilizing or encapsulating an ophthalmological drug andproviding a prolonged exposure to the surface of the eye. This prolongexposure may allow the drug to be both longer acting and increase thepenetration of the drug into the eye. Ophthalmological drugs suitablefor use in the present invention include, but are not limited to,diquafosol, cyclosporine, a prostaglandin, an antibiotic, anon-steroidal anti-inflammatory, a steroidal anti-inflammatory or acombination thereof.

In another preferred embodiment, the present invention is directed to anophthalmological drug delivery means, preferably selected from the groupconsisting of contact lenses, punctum plugs and pellets, coated orinfused with the compositions of the present invention.

In another embodiment, ophthalmological drug compositions of the presentinvention include standard dropper bottles, multi-dose preservative freebottles and unit dose delivery.

In another preferred embodiment, the present invention is furtherdirected to methods of increasing drug residency time on the surface ofthe eye comprising the steps of:

suspending or dissolving an ophthalmological drug in a composition ofthe present invention to create an ophthalmological drug composition;and

instilling the ophthalmological drug composition in the eye of a subjectin need thereof.

In a preferred embodiment, the active agent for the treatment of dry eyeachieves greater efficacy via residence time and permeation; and greaterefficacy via vehicle sequestration of induced tearing.

In another preferred embodiment, the present invention is furtherdirected to methods of reducing ocular infections comprising instillingthe composition of claim 1 into the eye of a subject in need thereof.

In another preferred embodiment, the present invention is furtherdirected to methods of treating dry age-related macular degeneration,wet age-related macular degeneration or diabetes comprisingadministering to a subject in need thereof an ophthalmological drugvehicle of the present invention.

In another preferred embodiment, the present invention is furtherdirected to a topical drug vehicle composition comprising a topical drugand one or more nonionic surfactants and at least one excipient selectedfrom a viscosity enhancer, a polyol and an electrolyte, preferably theophthalmological drug is selected from the group consisting ofcyclosporine, a prostaglandin, an antibiotic, a non-steroidalanti-inflammatory, a steroidal anti-inflammatory, GLC and a combinationthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 . Graph of Moisture-Lock™ Index versus nonionic surfactantconcentration. Moisture-Lock is a trademark owned by PS Therapies, Ltd.

FIG. 2 . Graph of Moisture-Lock™ effect values over time for various %w/v nonionic surfactant concentrations.

FIG. 3 . Shear rate of a composition containing 5.0% w/v poloxamer 407and 0.75% w/v high molecular weight carboxymethyl cellulose.

FIG. 4 . Schirmer's test of tear volume after installation ofComposition #C12 and Restasis®.

FIG. 5 . Average micelle size of Composition #C12, panel A, andRestasis®, panel B.

DETAILED DESCRIPTION OF THE INVENTION Discoveries of the Invention

Artificial Tears

The present invention is directed to the surprising discovery thatartificial tears can be formulated to cover a sufficient surface area ofthe eye to create an evaporative tear shield that can stabilize theaqueous and lipid layers of the tear film without the addition oflipids. Particularly surprising is the discovery that totalconcentration of nonionic surfactants may be increased in the presenceof the compositions of the present invention to well above 1.0% w/v,which has been demonstrated as toxic in prior art ophthalmologicalpreparations. Even more surprising is that compositions of the presentinvention with total nonionic surfactant concentrations up to 7.0% w/vmay be routinely instilled in the eye without toxicity. Further,compositions of the present invention surprisingly cause an evaporativetear shield to form and can be formulated to induce natural tearing thatis maintained under this evaporative tear shield. The discovery of suchcompositions is novel because present artificial tears that includelipids do not create an evaporative tear shield and leave an oily,unnatural feeling. Further, the artificial tear compositions of thepresent invention stabilize the lipid layer of the tear film as well asstabilize and spread the aqueous layer. Components of all three layersof the tear film are critical to successful tear function. Finally, theshape of the nano-micelles formed by the artificial tear compositions ofthe present invention provides an improved barrier to evaporation bycovering a substantial portion of the surface of the eye. Thesenano-micelles may be from about 12 to about 20 nanometers in diameter,from about 12 to about 14 nanometers in diameter, from about 15 to about20 nanometers in diameter or about 19 nanometers in diameter.

In detail, the presence of the nano-micelle layer, created usingnonionic surfactants at a particular concentration range, consists of anonpolar and a polar surface. This dual surface allows compositions ofthe present invention to not only stabilizes the natural lipid andaqueous layers of the tear film, but also create an evaporative barrier.The nano-micelle layer finds its preferred lowest energy level whenagainst any hydrophobic surface by spreading along that interface.Hydrophobic surfaces of the eye include both the original tear lipidlayer and the air-tear interface. Perhaps most important is the effectprovided by these specific interactions. Specifically, the 1) nonpolarseal, 2) polar and nonpolar stabilization of lipid and aqueous layers,3) improved spreadability per blink, and 4) greater tear film prismprovided by the compositions of the present invention create what iscalled the Moisture-Lock™ effect. The Moisture-Lock™ effect can bequantified somewhat with tear volume analysis via Schirmer's stripmeasurement or phenol thread. However, these tests are notoriouslydifficult to use accurately due to the many environmental variablesincluding reflex tearing that can compromise these measurements. A moreaccurate representation of the effect is a qualitative measure of theduration of added wetting felt=. This has been found to be particularlysensitive to the particular combination of nonionic surfactantcomponent(s) of the present invention, and more particularly to thetotal concentration of nonionic surfactants. Further, the viscosity ofthe composition and additional excipients play an important role in thepresent invention for a range of conditions that require these variablesto be customized. However, analyzing the Moisture-Lock™ effect withthese variables fixed produces a well-defined range where theMoisture-Lock™ effect occurs. See Example 1 below.

The Moisture-Lock™ effect results from any natural secretion of tearcomponents and particularly aqueous components being sealed under thenano-micelle layer created by compositions of the present invention.Such sequestration creates prolonged contact of critical aqueous factorsresulting in great therapeutic and comfort benefits, much like foundwith blood serum eye drop application. It has been discovered that amild to extreme degree of the Moisture-Lock™ effect may be triggered bycreating even slight tearing, such as by adjusting pH or osmolarity,which then becomes amplified by the tear sequestration property of thepresent invention.

Equally important, the concentration ranges and unique combinations ofparticular nonionic surfactants utilized in the present artificial tearcompositions dissolve lipids that would otherwise plug Meibomian ducts.Meibomian ducts are responsible for secreting components of the naturaltear that reduce tear evaporation. This clinical condition, known asMeibomian gland dysfunction, plagues not only many dry eye patients, butis a common affliction of glaucoma patients and others that mustcontinually use eye drops.

Artificial tear compositions of the present invention also, stimulatesecretion of the aqueous component of the natural tear. The evaporativeshield created then prevents evaporation of this natural aqueous layerin what is felt by the patient as the Moisture-Lock™effect. The neteffect of the stimulation of the natural tear, in combination with theability to sequester it, may provide greater additional exposure of theeyes to natural tear elements than that provided by prescriptionmedications such as Restasis® and Xiidra® (Restasis is a registeredtrademark of Allergan, Inc. and Xiidra is a registered trademark ofSARcode Bioscience Inc.). In clinical studies, Restasis® and Xiidra®have each been found to only marginally enhance tear production withmixed clinical results in treatment of dry eye (i.e. 50% or less benefitrequiring many months and often not or only marginally clinicallysignificant over conventional artificial tears).

Compositions of the present invention provide an extensive shield thatseals in natural tear production via the discovered means of tearsequestration. Even the slightest trigger of natural tearing, which maybe induced by pH adjustment, osmolarity adjustment, or addition ofcomponents such as menthol, may create an amplified benefit of thepresent invention by exposing the eye to greater volumes of naturaltears. This tear volume exposure is greater than that provided byRestasis® or Xiidra®, which increase tear volume by natural tearsecretion only. Further, these topical medications are prescription innature and extremely costly at as much as $300 per month. However, thepresent invention discovers novel means of combining generally regardedas safe ingredients to formulate an artificial tear composition withtruly surprising and unexpected results over these prior artformulations.

Artificial tears are traditionally an external source of lubrication forthe eye. However, the present artificial tear compositions further sealin natural tears for prolonged contact and wetting of the surface of theeye exposing the eye to growth factors, lysozymes, and other tearconstituents that help heal and protect the eye. Not wishing to be heldto a particular theory, the protective shield provided by the presentartificial tear compositions decrease tear wetting angle with formationof large tightly packed nano-micellar structures sealing the entiresurface area and providing the unexpected result of a Moisture-Lock™effect. This effect has not been possible with any previous generationof artificial tear. The Moisture-Lock™ effect is equivalent totriggering natural tear synthesis for prolonged periods of time andpossibly more substantial than plugging the punctal duct. Punctal ductplugging sequesters any tears a dry eye patient releases with reducedfrequency and or less effectively than compositions of the presentinvention. Further, compositions of the present invention nominallytrigger, sequester, and restrict tear drainage in the eye with only zeroto tens of seconds of visual blur even for the most extreme viscosities,which are only necessary for the most extreme therapeutic needs. This isin stark contrast to prior art formulations, which for example at 400centipoise requires ten or more minutes of visual blur to stabilize.

In a preferred embodiment, the present invention is directed toartificial tear compositions comprising one or more nonionic surfactantsand an electrolyte such that the compositions achieve desired fluid flowand non-Newtonian (nonlinear vs. lid shear) viscosity properties thatare dramatically affected by electrolyte concentration and optimized byelectrolyte concentrations that are preferably hypo-osmolar.

In another preferred embodiment, the present invention is furtherdirected to an artificial tear composition capable of increasingduration of the artificial tear composition on the eye and stabilizingthe natural aqueous and lipid layers. Preferably, the compositionfurther increases duration of exposure of the eye to the stabilizednatural aqueous layer including growth factors, antimicrobial factors,and other proteins and nutritional elements.

The benefits incurred from this prolonged exposure to the aqueous layeris currently possible only by spinning down blood and storing bloodplasma or platelet rich plasma followed by topical instillation to theeye. The benefits from this prolonged exposure to the natural aqueouslayer may be partially assessed by measure of the tear breakup time.However, tear breakup time is an antiquated means to quantify tearfunction and has less clinical relevance than the actual amount andduration of exposure of the corneal epithelium to the nutritional richaqueous layer. Commercially, the leading market dominating formulations(Allergan® Refresh® product line) demonstrate the most refreshingsensation of added moisture rather than a synthetic oily feeling. Forthe present invention, a ‘Moisture-Lock™ Index’ described in Example 1below better correlates with extent and duration of this importantsensation for an artificial tear to be most tolerated and desired.

In another preferred embodiment, the present invention is furtherdirected to a method of treating dry eye comprising administering acomposition of the present invention to an eye of a subject in needthereof, wherein administration provides sequestration of a tear layerunder a nonionic surfactant layer and preferably, wherein the nonionicsurfactant layer allows the retention of the aqueous layer via thehydrophobic outer layer aligning with the hydrophobic lipid layer orair. This layer is impervious to water permeation and provides ahydrophilic opposing surface. This opposing surface stabilizes theaqueous layer, and results in the aqueous constituents of normal andinduced tears, as well as the therapeutic constituents of the presentinvention such as the polyol and the electrolytes to maintain prolongedcontact with the eye.

A further advantage of the present invention is the surprising discoverythat addition of viscosity enhancers, particularly cellulosederivatives, carbomers, gums, dextrans, polyvinyl alcohol, polyacrylicacids, povidone, polyethylene glycol, propylene glycol, chitosans, andhyaluronates and hyaluronic acids, provides a low shear non-Newtonianhigh viscosity between blinks and high shear low viscosity duringblinks. The low shear viscosity between blinks helps spread the presentartificial tear compositions over the eye and the high shear viscosityduring blinks prevents the break up and drainage of the evaporativeshield. Thus, the ability to change in viscosity helps amplify theMoisture-Lock™ effect by strongly retarding tear evaporation anddrainage. Further, the addition of particular viscosity agents of thepresent invention provides a viscosity of 300-400 centipoise (“cps”) oninstillation, yet within 60 seconds no longer result in visual blur.Further, these viscosity agents provide a differential of about 70 cpsbetween blinks (low shear conditions) and below 30 cps, preferably below20 cps, during each blink (high shear conditions.) This is about tentimes quicker than the vision recovery of similarly viscous conventionaldrops such as Refresh Celluvisc®.

A still further discovery of the present invention is inclusion of apolyol and electrolytes that may protect the surface of the eye andfacilitate healing. These additional excipients may also reduce effectsof preservative toxicity from other prescribed drops such asantibiotics, steroids, nonsteroidals and or glaucoma drops. The presentinvention discovers that concentrations of polyols above about 0.5% w/vand, particularly, above about 1.25% w/v are preferred.

In summary, surprising discoveries of the compositions of the presentinvention include:

-   -   i) creation of a nano-micellar layer with sufficient surface        coverage to provide a substantial evaporative shield by        utilizing nonionic surfactant concentrations above the critical        micellar concentration of 10⁻³ M to 10⁻⁴ M from about 1.5% to        about 7.0% w/v and preferably less than about 5.5% w/v;    -   ii) dissolution of lipids and or lipid deposits on the surface        of the eye or contact lens by adding a polyoxyl at greater than        about 0.005% w/v but less than about 0.20% w/v, and more        preferably from about 0.01% to about 0.10% w/v, and most        preferably adding polyoxyl castor oils;    -   iii) provision of a composition that has high viscosity on        instillation that quickly equilibrates to normal tear viscosity        and then fluctuates between normal and high viscosities between        and during blinks, respectively, by adding particular viscosity        agents thus reducing vision blur and prolonging the duration of        the composition on the eye; and    -   iv) provision of additional benefits including possible        improvement in nerve regeneration and epithelial healing by        adding a polyol and magnesium ions in the form of salts.

Prior to the present invention, nonionic surfactants were used at verylow concentrations in artificial tears or as storage/soaking solutionsfor contact lenses. It was thought that the use of nonionic surfactantsat the concentration ranges of the present invention was too toxic fortopical application. It is a discovery of the present invention that theinclusion of the unique combination of nonionic surfactants at a totalconcentration from about 1.25% to about 7.0% w/v, preferably from about1.5% to about 6.0% w/v, from about 2.8% to about 5.9% w/v, from about2.0% to about 4.0% w/v, and from about 3.0% to about 3.5% w/v, a polyolat a concentration of about 0.5% w/v or greater, and a viscosity agentproviding a viscosity of 10 cps or greater, prevents toxicity.

Several over-the-counter (“OTC”) drops provide an external source oflipid components of the natural tear. These drops include: Soothe® XP(Soothe is manufactured by, available from and a registered trademark ofBausch & Lomb Incorporated) and Retaine® (Retaine is manufactured by,available from and a registered trademark of OcuSoft, Inc.), which eachcontains light mineral oil and mineral oil; Systane Balance® (SystaneBalance is manufactured by, available from and a registered trademark ofAlcon, Inc.), which contains propylene glycol; and Refresh Optive®Advanced (Refresh Optive is manufactured by, available from and aregistered trademark of Allergan, Inc.), which contains carboxymethylcellulose sodium, glycerin and polysorbate 80.

These OTC tear formulations have the disadvantage of: 1) minimalnonionic surfactant stabilization of the natural lipid layer, 2) minimalreduction of wetting angle to enhance spreading of the aqueous layer, 3)insufficient nonionic surfactant for the discovered advantages ofimproved nano-micelle geometries and 4) required surface area coveragefor evaporative shield protection.

It has been surprisingly discovered that the compositions of the presentinvention create a “welling of tears” for prolonged periods of time,reflected in creation of a large tear prism thickness along the lowerlid margins. Without wishing to be held to a particular theory, it isbelieved natural and, in some compositions, induced tearing remainssequestered under a low evaporative nanomicellar robust shield creatingan increased thickness of the aqueous layer and stabilized lipid layer.The sensation is further enhanced in most compositions of the presentinvention by the nonlinear (non-Newtonian) viscosity with increasedinterblink thickness and very low wetting angle, so that tears tend notto cross the hydrophobic air interface or run down the cheeks despitethe larger tear prism along the lid margins. Where conventional tearsmay produce some additional comfort and lubrication for 10-20 minutes,the disclosed invention results in a novel sensation for an hour orlonger. This novel sensation is the feeling of trapped tears, resultingfrom the lining of both lids flooding with moisture to the extent of anoverflow onto the lid margin for as long as 60 minutes. As a result, aunique phenomenon of prolonged trapping of tears, with great therapeuticpotential consequence and an extremely refreshing sensation for a dryeye patient of a “welling of tears” is produced. This phenomenon, hereinhereafter referred to as the Moisture-Lock™ effect and is measured bythe Moisture-Lock™ index.

It is believed that the total nonionic surfactant concentration rangecreates a micellar layer that becomes sufficiently packed todramatically cover the ocular surface and spread at an extremely lowwetting angle acting like a lipid and aqueous stabilizer. This layeralso spreads along the air or lipid hydrophobic interface aligning thenonpolar ends to create a robust non-evaporative surface. It issurprisingly discovered that at a critical concentration above thecritical micellar concentration (“CMC”) of the added nonionicsurfactant(s) there is therein created a concentration micelle trigger(“CMT”), which triggers confluence or near confluence along the ocularsurface and reduced evaporation without needing the addition of lipidsthat give a synthetic oily feeling. Further, this CMT is surprisinglydiscovered to occur in a range which is about 15 to 600 times above eachof the CMCs of the nonionic surfactant(s) resulting in the discoverednon-evaporative shield and the resultant Moisture-Lock™ effect. Thiseffect is maintained to a peak within this range and at an upperconcentration limit (“CUL”) begins to have surface toxicity as well asreduced effect. This reduced effect is possibly a result of a change inthe geometric configuration of the micellar layer(s).

It is believed the micellar layer at or above the CMT provides aconcentration range with the CUL as its upper limit within which acoating/shield effect results with two or more of several observed novelproperties:

-   -   i) creation of an evaporative shield causing reduced evaporation        of the tear layer and less sensitivity to humidity, tear volume,        or the tear breakup time, (tear breakup time is determined by        tear chemistry driven beading vs. time and is a difficult        variable to measure accurately because it is influenced by        irritation and other factors);    -   ii) providing extremely low surface tension for most immediate        coverage of the corneal surface and any dellen (i.e. irregular        topography along the corneal epithelium that creates dry spots);    -   iii) a non-Newtonian fluid flow resulting in substantial stasis        between blinks and easy flow during blinks primarily along the        high shear vertical component of that blink, such that lacrimal        drainage is minimized and tear film coverage along the corneal        surface is optimized with recycling on each blink until the lid        cul de sac depot of novel tear fill becomes slowly depleted;    -   iv) no blur at lower viscosities and only slight blur for about        15 seconds or less even at viscosities as high as 400 cps,        whereas conventional tear products (Liquigel® 150 cps,        Celluvisc® 400 cps) result in blurred vision for about a 10 to        20-minute range, respectively, thus providing benefits above and        beyond very viscous tear substitutes of conventional tear        formulations with the comfort and vision of very minimally        viscous conventional tears;    -   v) sequestration, meaning an apparent “trapping” of produced        tears under the non-evaporative shield unlike that found in        conventional tears that results in a “welling up” effect along        the lid margins for tens of minutes, and under conditions of        added viscosity agent with enhanced nonlinear non-Newtonian        shear effect of as much as an hour or longer, with provision of        prolonged contact of human tear constituents with the corneal        epithelium;    -   vi) sequestration as in v above of induced natural tears,        particularly in preferred embodiments where low pH, altered        osmolarity, or addition of excipients such as menthol result in        such induction and long duration retention;    -   vii) added comfort, epithelial protection, and enhanced milieu        for regenerative epithelial surface integrity by the addition of        excipients in the form of a polyol and or magnesium ions;    -   viii) a coating that once placed on a contact lens before        insertion provides a long-lasting coating effect that reduces        deposits on the contact lens surface and enhances vision on        instillation and facilitates improved comfort when instilled        during wear, particularly at least 16 hours after instillation        of the contact, thus reducing epitheliopathy, with minimal tear        dispersion surprisingly discovered for at least 24 seconds        compared to a normal tear breakup at 8 seconds;    -   ix) protection from saponification, as occurs in Meibomian gland        dysfunction, reducing the accumulation of lipid deposits that        stick to the palpebral conjunctiva and are difficult to remove,        as well as irritating moieties within the tear film, including        but not limited to cholesterol esters, preservatives from other        drops that may be concomitantly prescribed or required for        treatment of other conditions—such as particularly antibiotics,        nonsteroidals, steroidals, and glaucoma topical medications; and    -   x) a cumulative effect from the combination of two or more of        noted features above that improves comfort and health of the        corneal surface, allowing growth factors from tears to provide        prolonged beneficial protection and healing benefits for a        variety of external surface related physiologic stresses and        disease states.

Not wishing to be held to a particular theory, it is believed that mostnonionic surfactants available for ophthalmic use including, but notlimited to, polysorbate 20, 60, and 80; tyloxapol, poloxamer 188 and407; polyoxyl 30 and 40 castor oil; cyclodextrins includinghydroxypropyl-gamma-cyclodextrin, gamma cyclodextrin, Brij® 35, 78, 98,and 700 (polyoxyethyleneglycol alkyl ethers; Brij is a registeredtrademark of Uniqema Americas LLC); Span®20, 40, 60, and 80 (sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monostearate, and sorbitanmonooleate; Span is a registered trademark of Uniqema Americas Inc.), orcombinations thereof in the concentration range of about 1.5% to about5.5% w/v and where the critical micellar threshold ranges from about1×10⁻³ M to 1×10⁻⁴ M, have been discovered to result in importantcharacteristics such as:

-   -   i) lowest energy geometries via layering due to the        juxtaposition of hydrophobic surfaces upon instillation onto the        eye—from closest to furthest from the ocular surface being        epithelium, lipid layer and air interface;    -   ii) lowest energy geometries via layering due to juxtaposition        to one or more hydrophobic surfaces upon instillation onto the        eye to which they may be exposed including: corneal and        conjunctival epithelium, natural lipid tear film layer and air        interface, or similarly become so densely packed as to        effectively function as a protective shield, or coating;    -   iii) sufficient density within the preferred concentration range        that when layered or densely packed on top of the aqueous layer        it retards evaporation significantly;    -   iv) smoothing out of the lipid layer to retain a smoother more        uniform surface and dissolving Meibomian gland lipids to further        increase its thickness;    -   v) superior spreadability due to the low surface tension and        wetting angle and coating of the epithelial surfaces with each        high shear blink, particularly dellen (elevated regions of        corneal topography tear film may not coat evenly or at all);    -   vi) providing one or more nonionic surfactants whereby each of        the above functions may be facilitated by different surfactants,        and where the concentration range of about 1.5% to about 5.5%        w/v represents the aggregate summation of individual surfactant        concentrations; and    -   vii) where polyoxyls and particularly polyoxyl castor oils may        preferentially solubilize Meibomian gland secretions.

A further surprising discovery of the present invention is the prolongedMoisture-Lock™ effect of even mild hyperosmolarity, such as provided byincreasing concentrations of the electrolyte to about 0.20% w/v orabove. In particular, sodium chloride is preferred for this purpose. Itis believed the very gentle but slight irritation created by ahyperosmolar tear triggers an initial increase in tearing, which becomes“locked” under the micellar layer. This tear secretion is then furthersealed by non-Newtonian flow properties providing valuable inotropicgrowth factors and other nutrients and physiologic components to thesurface of the eye. These non-Newtonian flow properties provide sealingby limiting lacrimal drainage via increased viscosity at the low shearbetween blinks while improving visual acuity by the low viscositytriggered at the high shear during a blink.

An additional surprising finding is the novel discovery that a polyol,particularly mannitol, and or magnesium ions, and particularly thecombination provide protection of the corneal surface fromepitheliopathy, including but not limited to the effects ofpreservatives and or antioxidants.

An additional unexpected finding is that the addition of an antioxidantadds increased duration of effect. This discovery is surprising in lightof the long-held tenet that tear formulation antioxidants, particularlyEDTA, cause epithelial toxicity.

Variations in the a) concentration, particularly of viscosity agent(s),b) epithelial protective excipients such as polyols such as mannitol andc) addition of electrolytes particularly magnesium ions and NaCl providea means to titrate duration of wetting effect (i.e. Moisture-Lock′effect), degree of initial blur (i.e. from about 0 to 15 seconds), and arange of other effects including protective and therapeutic effects.This variability of compositions of the present invention allowtreatment of a range of conditions.

Certain conditions, such as meibomian gland dysfunction (“MGD”) maybenefit from lid massage and oil expression techniques, such as a cottonball roll along the lid margins. These conditions may also benefit fromthe robust nonionic surfactant surface layer created in the CMT rangefor the total nonionic surfactant concentration (i.e. from about 1.5% toabout 5.9% w/v, more preferably from about 2.5% to about 4.0% w/v).Where increased concentrations of particular nonionic surfactants suchas polyoxyls, preferably polyoxyl castor oils, and most preferablypolyoxyl 30 or 40 castor oil at a concentration from about 0.001% toabout 2.0% w/v, and more preferably from about 0.010% to about 1.0% w/vmay further enhance such formulations for treatment of MGD. It isadditionally discovered that addition of a polyethylene glycol oilenhances the stability of the composition.

The present invention combines a high degree of mucoadhesiveness andtemperature sensitive alteration in rheological properties between andduring blink. These rheological properties allow for physiologicblinking without blur, and after equilibration, within about 15 to 60seconds depending on the embodiment selected, creates a thin tear filmof about 5-10 μm. It has been surprising that the present invention:

-   -   a) creates prolonged wetting and hydration typically of about        one hour or longer;    -   b) creates minimal blur on instillation of tens of seconds,        typically 30 seconds or less (See Table 2 above);    -   c) produces no crusting of lids or lashes, only a prolonged        wetting action felt along lid margins;    -   d) allows comfortable instillations at very low (less than 4) or        high (greater than 7) pH;    -   e) provides prolonged tear sequestration and exposure to induced        (Moisture-Lock™ effect) and natural tears via the robust        hydrophobic barrier of the nonionic surfactant layer (See Table        13 and FIGS. 1 and 2 ); and    -   f) provides potential for equal or greater incremental tear        exposure to the ocular surface than current generation        prescription dry eye products Restasis® and or Xiidra®, which        demonstrate only marginal incremental increase in tear        secretion.

Excipients of the present invention that may reduce epithelial toxicityinclude one or more of polyols and electrolytes, where it issurprisingly discovered that the combination of nonionic surfactants ofthe present invention is further enhanced by from about 0.10% to about2.00% w/v NaCl, more preferably from about 0.20 to about 2.00% w/v, andmost preferably from about 0.25% to about 2.00% w/v. Normal isotonicsolutions would typically require 0.90% w/v NaCl. A second electrolytein preferred embodiments is magnesium ions. In a more preferredembodiment, the source of magnesium ions is MgCl₂. In an even morepreferred embodiment, the MgCl₂ is at a concentration from about 0.01%to about 0.25% w/v, more preferably from about 0.05% to about 0.15% w/v,and most preferably from about 0.075% to about 0.125% w/v. The polyol ispreferably mannitol and more preferably mannitol is at a concentrationfrom about 0.25% to about 4.0% w/v, even more preferably from about0.75% to about 4.0% w/v, more preferably from about 1.5% to about 4.0%w/v. Not to be held to a particular theory, it is believed theseexcipients, alone or in combination, enhance epithelial healing,recovery of injured neuronal components, reduce pain, promote quickerepithelial surface smoothing and health, and reduce or eliminatesuperficial punctate keratopathy. Superficial punctate keratopathy is acommon ocular surface abnormality from exposure to irritants. Theseirritants are particularly preservatives found in most eye dropsincluding antibiotics, steroids, nonsteroidals, and glaucoma drugs.Accounting for toxicity after cataract surgery due to these irritantsand for those on medications for chronic eye diseases, such as glaucoma,the compositions of the present invention may considerably alleviateassociated symptoms.

The present invention benefits from a total surfactant concentration ofat least 1.0% w/v, preferably from about 1.0% to about 10% w/v, morepreferably from about 1.0% to about 5.9% w/v, even more preferably fromabout 1.5% to about 5.9% w/v, even more preferably from about 2.5% toabout 5.5% w/v, and most preferably from about 3.0% to about 5.0% w/v,where the nonionic surfactant or nonionic surfactants each have acritical micellar concentration (the concentration at which micelleformation occurs and surface tension is no longer reduced) in the rangeof 10⁻³ to 10⁻⁴ M. The nonionic surfactant may consist of one or more ofcyclodextrins (where hydroxy propyl gamma cyclodextrin, gammacyclodextrin, and beta cyclodextrin are most preferred); polyoxylsorbates, including all Tween® sorbates (polysorbates; Tween is aregistered trademark of Uniqema Americas, LLC), including Tween® 80, 60,40, or 20; other polyoxyls (most preferred being polyoxyl castor oilsand polyoxyl stearates); alkyl aryl polyethers (most preferred beingtyloxapols); alkyl ethers including all Brij® alkyl ethers (mostpreferred being Brij® 35, 78, 98, and 700; Span® 20, 40, 60, and 80(sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate,and sorbitan monooleate) and tocopherols (Vitamin E).

The non-Newtonian viscosity component is increasingly importantproportional to the clinical need for treatment of a dry eye or dry eyerelated condition. The non-Newtonian viscosity component is especiallyimportant in the absence of an inserted device including contact lensesand punctum plugs. The non-Newtonian viscosity component providesreduced tear drainage between blinks when the viscosity is at more thanabout 30 cps, preferably from about 35 to about 50 cps, and mostpreferably from about 70 to about 400 cps between blinks; and duringeach blink less than about 30 cps, preferably less than about 25 cps,and most preferably about 20 cps or less. In a preferred embodiment, thenonlinear shear viscosity ratio is from about 5:1 to about 10:1interblink to blink viscosity. Surprisingly the combination of nonionicsurfactant in the preferred range and viscosity agents at low (less thanabout 20 cps or up to about 500 cps) creates a surprising equilibrationof vision at high viscosity and improved flow properties. Commercialhigh viscosity tear formulations such as Refresh Celluvisc®, also at 400cps have been shown in numerous studies to require 10-15 minutes toequilibrate to normal vision, over ten times longer than the surprisingdiscovery of preferred nonionic surfactant(s) and viscosity agentsbetween 10 cps and 500 cps of the present invention. Viscosity agentsfor preferred embodiments of the present invention including, but notlimited to, cellulose derivatives such as HPMC, HPC, HPEC and CMC;Carbopol® compounds such as Carbopol® 90 and 940; hyaluronates; and gumssuch as guar and locust gums.

It is a surprising discovery of the present invention that applicationof preferred embodiments, particularly formulations utilizingpolysorbates, poloxamers, polyoxyls or cyclodextrins alone or incombination with each other and or other nonionic surfactants haveproperties of optimized tear film moisture retention. See FIG. 1 . Evenmore unexpected, use of viscosity agents, particularly cellulose agentsand or their derivatives, and more particularly hydroxypropyl methylcellulose or carboxymethyl cellulose or carbomer 940 dramaticallyenhance tear film moisture retention and even at resting low shearviscosities in their packaged delivery bottle or unit dose tube as highas 200-400 cps have only transient blur of a few seconds to under 30seconds. This tear film moisture retention is known herein as MoistureLock™. It is still more surprising that storing of soft contact lenses,including but not limited to those consisting of silicone and orhydrogel polymers, in blister packs, or other packaging that retains aliquid, with compositions of the present invention results in asubstantial adherence of the composition to the contact lens surfacereducing deposits. Once these contacts that were stored in thecompositions of the present invention are placed on the eye of thesubject the composition greatly increases tear break up times whilereducing tear dispersion. This adherence creates a strongly bondednon-evaporative coating that stabilizes the tear film, increases comfortand provides an optional dry eye therapy even for contact lensintolerant subjects.

Artificial tear compositions 36-57 of Table 2 and 58-89 of Table 3 offersuperior wetting and Moisture-Lock™ effect over artificial tearcompositions 1-35 of Table 2. This superior effectiveness ishypothesized to be caused by the unique combination and concentrationsof nonionic surfactants. Further, the addition of a polyol and magnesiumions to compositions 36-57 is hypothesized to further enhance wettingand Moisture-Lock™ effect over those compositions that do not contain apolyol and magnesium ions.

There clearly appears to be surprising effects within the combinations,concentrations and ratios of the invention. Particularly nonionicsurfactant ranges and combinations, in relation to viscosity,electrolytes and protective excipients such as a polyol and magnesiumions provide surprising effects. Particularly surprising is the relationof electrolytes to final viscosity, blur or lack thereof, and comfort.Preferred embodiments result in increased tear film stability, prolongedMoisture-Lock™ effect and welling up of the aqueous layer from many tensof minutes to up to one hour with a single drop. Relative to theviscosity there is reduced time of blurred vision when compared tocurrent artificial tears and more prolonged and clinically improvedeffect for a great variety of conditions.

Ophthalmological Drug Vehicles

A further surprising discovery of the present invention is thatophthalmological drugs added to the present invention increase durationof the drugs on the surface of the eye, increase permeation across thecornea, and reduce systemic absorption, creating an ideal platformvehicle for drug delivery while reducing dry eye symptoms and irritationthat might otherwise occur for many such active agents such asnon-steroidals, antibiotics, and glaucoma drugs. This drug vehicle maybe particularly useful for enhancing the therapeutic duration andbenefits of cyclosporine-A currently found in Restasis®. Thesecompositions may be capable of formulating up to 0.09% and from about0.05% to about 0.09% cyclosporine-A without the need to create anemulsion. In a preferred embodiment, the cyclosporine-A drug vehicles ofthe present invention may not contain emulsifiers. The cyclosporine-Adrug vehicle of the present invention provides from about 12 to about 20nanometer diameter nano-micelles. Further, the cyclosporine-A drugvehicle of the present invention delivers suffusion of tears for up to60 minutes.

A further surprising discovery of the present invention is thesuppression of preservative toxicity effect resulting from one or moreof preservatives in the presence of the present invention, particularlytherapeutic excipients such as a polyol and or magnesium ions. Thisdiscovery is surprising in light of the long-held tenet that tearformulation preservatives cause epithelial toxicity and is potentiallyof great importance as many chronic use ophthalmic drugs, such as forglaucoma, or inflammation are compromised by the accrued effect ofinduced epithelial toxicity often limiting their duration of use.

A further surprising discovery of the present invention is the sustainedrelease of a drug. The peak concentration of the drug can be increasedabout 50% in duration, (e.g. from 2 to 4 hours).

Skin Compositions and Drug Vehicles

It is further discovered that compositions of the present invention maybe used in anesthetic gels, as an anti-adhesion for prevention ofscarring, in implantable devices, in time-release impregnated bandages,in parenterals, in inhalers, in sprays, in topical lotions, in topicalgels, in topical liquids, in anti-aging skin products such as day andnight product and under eye products, in sunscreens, in body wash, intherapeutic shampoos, in antiperspirant, for stretch marks, in shavingcreams, as a blade glide coating, in OTC lidocaine compositions, in OTCcortisone compositions, in Ben-Gay® like products including Ben-Gay®,for treating acne, in collagen-based products, in retinal-basedproducts, for treating dry skin, for treating dermatitis, psoriasis, forreducing or eliminating scars or port wine stains, for enhancing hairgrowth, as a non-irritating hair dye and for facial wasting disease.

It is unexpected that the ophthalmological compositions of the presentinvention could be used for prevention, treatment and minimization oreradication of aging and other imperfections in the skin. However, theadministration and use of a nanomicellar nonionic surfactant compositionwith a physiologically based pH, as disclosed herein, has the benefit ofproviding a cleansing, mildly exfoliating and reparative moisturizingeffect on facial tissue. The effect can deliver, based on a prescribedtreatment regimen, visible improvement in the areas of managing fine tomoderate wrinkling, lightening and size reduction of sun, age and/orliver spots on the skin.

The long-term moisturizing effect that penetrates the top skin layerscan also provide long term hydration for the skin which maintains skintone and texture. Further contemplated are eliminating of commonblemishes, reducing skin thickness (supporting use on scar removal overtime), improving dry skin as well as elasticity and collagen. Furthercontemplated as a use for the compositions of the present invention ismaintenance of normal pore size as well as the increase in hydration,which can also increase the tightness of the facial skin, thus improvingthe overall smoothness.

The compositions of the present invention may comprise droplets, andthese droplets may comprise an aqueous phase, at least one oil, a mix offour or more nonionic surfactants, at a specific concentration range, ina topically applied lotion or other compatible and pharmaceuticallyaccepted forms. In mild cases, this base composition may be used as thesole treatment method for the skin. However, in more severe cases, thehighly compatible base formula can be combined with any of the knownactive drug substances, such as Botox®, retinoids, and any other proventopical treatment. Specifically, the specific nonionic nanoparticlesenhance permeation into the top layers of the skin, which enhancesefficacy.

Within the liquid cleanser category, the least irritating cleanser willcontain non-ionic/silicone-based surfactants combined with moisturizers,as they will cause the least disruption to the moisture skin barrier andthe normal skin flora. While this describes cleanser qualities, thesesame benefits, plus some new findings, indicate that use after cleansingprovides benefit to a patient's skin conditions and, when used asdirected, can effectively manage a host of dermatologic conditions thatwould otherwise negatively affect self-esteem and social acceptance. Itis a discovery of the present invention that most issues surroundingaging skin can be effectively managed by the nonionic surfactant aloneor when combined with a specific active drug treatment used on the skin.

Definitions

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, from acombination of the specified ingredients in the specified amounts.

As used herein, all numerical values relating to amounts, weights, andthe like, that are defined as “about” each particular value is plus orminus 10%. For example, the phrase “about 5% w/v” is to be understood as“4.5% to 5.5% w/v.” Therefore, amounts within 10% of the claimed valueare encompassed by the scope of the claims.

As used herein “% w/v” refers to the percent weight of the totalcomposition.

As used herein the term “subject” refers but is not limited to a personor other animal.

Throughout the application, the singular forms “a,” “an,” and “the”include plural reference unless the context clearly dictates otherwise.

As used herein the term “polyol” refers to compounds with multiplehydroxyl functional groups available for organic reactions such asmonomeric polyols such as glycerin, pentaerythritol, ethylene glycol andsucrose. Further, polyols may refer to polymeric polyols includingglycerin, pentaerythritol, ethylene glycol and sucrose reacted withpropylene oxide or ethylene oxide.

As used herein the phrase “means for inducing tears” includes any meansby which production of natural tears may be induced in the subject towhich the compositions of the present invention are applied. Preferably,tears may be induced by modifying the pH of the composition to a rangefrom about 5.0 to about 6.0, modifying the osmolarity of the compositionto a range from about 350 to about 550 milliosmoles and or including aterpenoid, such as menthol.

As used herein the phrase “means for sequestering tears” includes anymeans by which natural tears induced by the compositions of theinvention and the artificial tears compositions of the invention may besequestered on the eye. Preferably, a combination of particularconcentrations and types of nonionic surfactants and particularconcentrations and types of viscosity enhancers are used as the meansfor sequestering tears.

Ingredients of the Invention

Nonionic surfactants that can be used in accordance with the presentinvention include, but are not limited to, poloxamers, polysorbates,cyclodextrins, alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers,tyloxapol, and polyoxyls. Poloxamers are nonionic triblock copolymerscomposed of a central hydrophobic chain of polyoxypropylene(poly(propylene oxide)) flanked by two hydrophilic chains ofpolyoxyethylene (poly(ethylene oxide)). Polysorbates are oily liquidsderived from ethoxylated sorbitan esterified with fatty acids.Cyclodextrins are composed of 5 or more α-D-glucopyranoside units linkedtogether at position 1 and 4. Polyoxyls are a mixture of mono- anddiesters of stearate and polyoxyethylene diols. Preferred embodimentsinclude but are not limited to poloxamers-poloxamer 188 and poloxamer407; polysorbates-polysorbate 20, polysorbate 60, polysorbate 80,tyloxapol, Brij® 35, Brij® 78, Brij® 98 and Brij® 700, Span® 20, Span®40, Span® 60, Span® 80; cyclodextrins-2-HP-cyclodextrin, ionicallycharged (e.g. anionic) beta-cyclodextrins with or without a butyratedsalt (Captisol®; (sulfobutylether β-cyclodextrin, Captisol is aregistered trademark of Cydex Pharmaceuticals),hydroxypropyl-gamma-cyclodextrin, gamma cyclodextrin; andpolyoxyls-polyoxyl 40 stearate, polyoxyl 30 castor oil, polyoxyl 35castor oil, and polyoxyl 40 hydrogenated castor oil; or combinationsthereof. Polyols are not included in the term “nonionic surfactants.”Total nonionic surfactant concentrations of the present invention arefrom about 1.0% to about 7.0% w/v, preferably, 1.5% to about 7.0% w/v,preferably from about 1.5% to about 6.0% w/v, more preferably from about1.5% to about 5.9% w/v, more preferably from about 1.5% to about 5.5%w/v, more preferably above about 2.0% w/v and less than 6.0% w/v, fromabout 2% to about 4% w/v, more preferably from about 2.5% to less thanabout 5.9% w/v, more preferably from about 2.5% to about 5.5% w/v, morepreferably from about 2.5% to about 3.5% w/v, more preferably from about2.8% to about 5.9% w/v, more preferably from about 3% to about 5% w/v,more preferably from about 3% to about 3.5% w/v.

In preferred embodiments, the one or more nonionic surfactants include apolysorbate, such as polysorbate 80.

In more preferred embodiments the amount of polysorbate is from about0.01% to about 4.0% w/v, preferably from about 0.5% to about 3.5% w/v,preferably about 0.5%, 1%, 1.5%, 2%, 2.5%, 2.75%, 3% and 3.5% w/v.

In other preferred embodiments, the one or more nonionic surfactantsinclude a poloxamer such as poloxamer 188 and or poloxamer 407, apolyoxyl such as a polyoxyl castor oil including polyoxyl 35 castor oilor polyoxyl 40 hydrogenated castor oil, a cyclodextrin, such ashydroxypropyl-gamma-cyclodextrin and tyloxapol.

In other preferred embodiments the one or more nonionic surfactantsinclude from about 0.01% to about 3.5% w/v poloxamer 407, preferably,from about 0.2% to about 3.5% w/v, preferably, about 0.1%, 0.2%, 0.7%,1%, 3% and 3.5% w/v.

In other preferred embodiments the one or more nonionic surfactantsinclude from about 0.01% to about 3% w/v poloxamer 188, preferably, fromabout 0.1% w/v to about 1% w/v, preferably about 0.01%, 0.1%, 0.2%,0.4%, 0.5% and 0.75% w/v.

In other preferred embodiments the one or more nonionic surfactantsinclude from about 0.001% to about 2.0% w/v polyoxyl castor oil,preferably, from about 0.005% to about 0.25% w/v, preferably, from about0.01% w/v to about 1% w/v, preferably, from about 0.01% to about 0.1%w/v, preferably, from about 0.15% to about 0.25% w/v, preferably about0.001%, 0.01%, 0.1%, 0.15%, 0.25%, 0.5% and 1% w/v.

In other more preferred embodiments, the one or more nonionicsurfactants include from about 0.01% to about 5% w/vhydroxypropyl-gamma-cyclodextrin, preferably from about 0.5% to about 5%w/v, preferably, from about 1.5% to about 3.0% w/v, preferably, about0.25%, 0.5%, 0.7%, 0.75%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4% and 5% w/v.

In other preferred embodiments, the addition of 0.005% to 4.0% w/vtyloxapol or from about 1.75% to about 3.00% w/v sorbitol may be addedin combination or as a replacement for the one or more nonionicsurfactants such that the total surfactant concentration does not exceed7% w/v;

In other preferred embodiments, the one or more nonionic surfactants mayinclude polyoxyl 35 castor oil at an amount from about 0.25% to about5.00% w/v; preferably from about 0.15% to about 0.25% w/v.

Viscosity enhancers that can be used in accordance with the presentinvention are non-Newtonian viscosity enhancers, which include, but arenot limited to cellulose derivatives, carbomers (Carbopol®), gums, andhyaluronic acids (hyaluronates), dextrans, polyvinyl alcohol,polyacrylic acids, povidone, polyethylene glycol, propylene glycol andchitosans; where for cellulose derivatives particularly preferred areone or more of carboxymethyl cellulose (“CMC”) high molecular weightblend, CMC low molecular weight blend, CMC moderate molecular weightblend, methylcellulose, methyl cellulose 4000, hydroxymethyl cellulose,hydroxypropyl cellulose (“HPC”), hydroxypropylmethyl cellulose highmolecular weight blend (“HPMC”), hydroxyl propyl methyl cellulose 2906,carboxypropylmethyl cellulose high molecular weight blend (“CPMC”),hydroxyethyl cellulose, or hydroxyethyl cellulose and hyaluronic acid,such that the concentrations cumulatively do not create a phasetransition to an in situ gel. The non-Newtonian properties afforded tocompositions of the invention by viscosity enhancers of this type can beseen in FIG. 3 , which demonstrates the during blink and between blinkdifference in viscosity. This viscosity can be modified to targetspecific clinical treatments. Specific viscosities and viscosityenhancers may achieve an intrablink (high shear rate) viscosity of about30 cps or less, more preferably about 25 cps or less, and mostpreferably about 20 cps or less. Specific clinical treatments may usethe following interblink (low shear rate) viscosities:

-   -   i. contact lens use: about 1 to about 5 cps;    -   ii. artificial tears mild-moderate dry eye: about 5 cps to about        100 cps;    -   iii. artificial tears moderate-severe dry eye: about 100 cps to        about 250 cps; and    -   iv. artificial tears severe dry eye: about 250 to about 5000        cps.

In preferred embodiments, the viscosity enhancing excipient is selectedfrom the group consisting of CMC low molecular weight blend, CMCmoderate molecular weight blend, CPMC, HPC, HPMC and carbomer 940 or acombination thereof.

In more preferred embodiments the amount of CMC is from about 0.05% toabout 1.75% w/v including 0.05%, 0.10% w/v, 0.20% w/v, 0.25% w/v, 0.3%w/v, 0.4% w/v, 0.5% w/v, 0.55% w/v, 0.62% w/v, 0.65% w/v, 0.75% w/v,1.0% w/v, 1.25% w/v, 1.35% w/v, 1.38% w/v, 1.40% w/v and 1.45% w/v.

In other more preferred embodiments, the amount of HPC is from about0.10% to about 1.75% w/v including 1.0% w/v, 1.25% w/v, 1.40% w/v, 1.50%w/v or 1.75% w/v.

In other more preferred embodiments the amount of HPMC is based on themolecular weight of Methocell® (Dow-Corning) from about 0.10% to about1.75% w/v, preferably from about 0.1% to about 1.5% w/v, from about 0.5%to about 1.25% w/v, from about 0.65% to about 1.0% w/v, from about 1% toabout 1.35% w/v, from about 1.25% to about 1.35% w/v, from about 1.35%to about 1.5% w/v, from about 1.35% to about 1.45% w/v, preferably about0.10% w/v, 0.20% w/v, 0.25% w/v, 0.3% w/v, 0.4% w/v, 0.5% w/v, 0.55%w/v, 0.62% w/v, 0.65% w/v, 0.75% w/v, 0.85% w/v, 1.0% w/v, 1.25% w/v,1.3% w/v, 1.35% w/v, 1.38% w/v, 1.40% w/v, 1.45% w/v and 1.48% w/v.

In more preferred embodiments the amount of carbomer 940 is from about0.01% to about 2.0% w/v, preferably from about 0.8% to about 1.3% w/vand more preferably at about 0.01%, 0.8% 0.9%, 1.1%, 1.2% or 1.3% w/v.

In certain embodiments polyvinyl alcohol (“PVA”) may be used as aviscosity enhancer in compositions of the present invention. Preferably,PVA is at a concentration of about 0.5% w/v.

In other embodiments, the present invention further comprises glycerinin an amount from about 0.05% to about 2.0% w/v; preferably from about0.1% to about 0.4% w/v.

Polyols suitable for use in the present invention include, but are notlimited to, mannitol, glycerol, erythritol, lactitol, xylitol, sorbitol,isosorbide, and maltitol. In a more preferred embodiment, the polyol ismannitol. In another more preferred embodiment, the polyol is at aconcentration from about 0.1% to about 4% w/v, from about 0.25% to about5.5% w/v, from about 0.25% to about 4.0% w/v, from about 0.25% to about2.5% w/v, from about 1% to about 4% w/v, from about 1% to about 2.5%w/v, from about 1.5% to about 3.0% w/v, from about 1.5% to about 2.5%w/v, from about 2% to about 2.5% w/v and about 1% and 2.5% w/v.

Electrolytes suitable for use in the present invention include, but arenot limited to, magnesium ions, sodium chloride (“NaCl”), potassiumchloride (“KCl”) and a combination thereof. In a more preferredembodiment, the magnesium ions are derived from magnesium chloride. Inanother more preferred embodiment, the total electrolyte concentrationis at a concentration from about 0.01% to about 2.0% w/v. In a morepreferred embodiment the magnesium ions are at a concentration fromabout 0.01% to about 0.25% w/v as MgCl₂, preferably about 0.05% to about0.15% w/v and from about 0.075% to about 0.125% w/v, and the NaCl is ata concentration from about 0.01% to about 2.0% w/v, preferably, fromabout 0.1% to about 2.0% w/v from about 0.2% to about 2.0% w/v, fromabout 0.25% to about 2.0% w/v, and more preferably about 0.01%, 0.2%,0.25%, 0.3%, 0.35%, 0.37%, 0.4%, 0.5%, 0.62%, 0.7%, 0.75%, 1.0%, 1.25%,1.5%, 1.75%, and 2.0% w/v, and the KCl is at a concentration from about0.1% to about 0.5% w/v.

Preservatives suitable for use in the present invention include, but arenot limited to, benzalkonium chloride (“BAK”), sorbate, methylparaben,polypropylparaben, chlorobutanol, thimerosal, phenylmercuric acetate,perborate, phenylmercuric nitrate and combinations thereof. In apreferred embodiment, the preservative is BAK, sorbate or a combinationthereof. In a preferred embodiment, the preservative is at aconcentration from about 0.005% to about 0.15% w/v. In a more preferredembodiment BAK is at a concentration from about 0.005% to about 0.02%w/v and sorbate is at a concentration from about 0.015% to about 0.15%w/v.

Antioxidants suitable for use in the present invention include, but arenot limited to, citrate. EDTA, sodium metabisulfite, sodium thiosulfate,acetylcysteine, butylated hydroxyanisole and butylated hydroxytolueneand a combination thereof. In a preferred embodiment, the preservativeis at a concentration from about 0.05% to about 0.2% w/v.

In certain embodiments, a terpenoid may be used in compositions of thepresent invention. In a preferred embodiment, a terpenoid includes, butis not limited to, citral, WS-12, icilin and menthol.

In certain embodiments menthol may be used in compositions of thepresent invention. Preferably, menthol is at a concentration from about0.01 to about 4.00 mM, from about 0.01 to about 2.0 mM, from about 0.025to about 0.07 mM, from about 0.07 to about 0.3 mM, from about 0.07 toabout 0.1 mM, from about 0.1 to about 0.40 mM, from about 0.1 to about0.2 mM, from about 0.15 to about 0.25 mM, from about 0.25 to about 2.0mM and about 0.01, 0.07, 0.1, 0.14, 0.15, 0.2, 0.27, 0.30, 0.32, 0.34,0.36, 0.37, 0.38, 0.40, 0.42, 0.44, 0.46, 0.48, 0.5, 0.6, 0.65, 0.7,0.75, 0.8, 0.85, 1.0, 1.2, 1.5, 1.6, 1.75, 2.0 or 4.0 mM.

Buffers and pH adjustors that can be used in accordance with the presentinvention include, but are not limited to, acetate buffers, carbonatebuffers, citrate buffers, phosphate buffers and borate buffers. In apreferred embodiment, the buffers and pH adjustors are at aconcentration from about 1 to about 100 millimolar, more preferably fromabout 3 to about 10 millimolar and most preferably about 3, 4, 5, 5.5,6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 millimolar It is understood thatvarious acids or bases can be used to adjust the pH of the compositionas needed. pH adjusting agents include, but are not limited to, sodiumhydroxide and hydrochloric acid. Surprisingly, pH has not been found toalter comfort in the artificial tears compositions. pH of thecompositions can be from 4.0 to 8.0, more preferably from about 5.0 toabout 8.0 and from about 5.0 to about 6.0, and less than 6.0.

Compositions of the Invention

The present invention discovers a narrow therapeutic range of non-ionicsurfactant(s) concentration(s) in a preferred embodiment requiringeither a non-Newtonian viscosity excipient(s), electrolytes or otherexcipients that provide improved epithelial protection and healing suchthat with regular use or even on a single instillation both comfort andefficacy are improved. The ingredients and concentrations of thecompositions represented herein are the best-known embodiments but arenot intended to be all inclusive.

Artificial Tears

In certain embodiments, the present invention is directed to artificialtear compositions comprising a means for inducing tears and a means forsequestering tears.

In a preferred embodiment, the means for inducing tears is selected froma pH from about 5 to about 6, a terpenoid and an osmolarity of fromabout 350 to about 550 milliosmoles.

In another preferred embodiment, the means for sequestering tearscomprises from about 1.5% to about 5.9% w/v total volume of one or morenonionic surfactants and one or more viscosity enhancers, wherein theone or more viscosity enhancers provides a viscosity of from about 50 toabout 10,000 centipoise at 0 shear to 1 second.

In more preferred embodiment, the one or more nonionic surfactants areselected from the group consisting of polysorbates, poloxamers, polyoxylcastor oils and combinations thereof.

In another more preferred embodiment, the one or more viscosityenhancers are selected from the group consisting of cellulosederivatives, carbomers, gums, and hyaluronic acids, dextrans, polyvinylalcohol, polyacrylic acids, povidone, polyethylene glycols, propyleneglycol, chitosans and combinations thereof, even more preferably the oneor more viscosity enhancers are selected from the group consisting ofcellulose derivatives, carbomers, polyvinyl alcohol, polyethyleneglycols and combinations thereof.

In another embodiment, the artificial tear compositions of the presentinvention further comprise a polyol, preferably selected from the groupconsisting of mannitol, xylitol, sorbitol, isosorbide, erythritol,glycerol, maltitol and a combination thereof.

In another embodiment, the artificial tear compositions of the presentinvention further comprise one or more electrolytes, preferably selectedfrom the group consisting of magnesium ions, sodium chloride, potassiumchloride and a combination thereof.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   one or more nonionic surfactants selected from the group        consisting of poloxamers, polysorbates, cyclodextrins, alkylaryl        polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and        polyoxyls at a total concentration from about 1.5% to about 6.0%        w/v; preferably the one or more nonionic surfactants are        selected from the group consisting of from about 0.01% to about        4.0% w/v of a polysorbate, from about 0.01% to about 3.5% w/v of        a poloxamer, from about 0.01% to about 2.0% w/v of a polyoxyl        and from about 0.01% to about 5.0% w/v        hydroxypropyl-gamma-cyclodextrin;    -   one or more viscosity enhancers selected from the group        consisting of cellulose derivatives, carbomers, gums, dextrans,        polyvinyl alcohol, polyacrylic acids, povidone, polyethylene        glycol, propylene glycol, chitosans, and hyaluronates and        hyaluronic acids; from about 0.01% to about 2.0% w/v of one or        more electrolytes selected from the group consisting of sodium        chloride, potassium chloride and magnesium ions, preferably, the        one or more electrolytes is selected from about 0.01% to about        0.25% w/v magnesium ions, from about 0.10% to about 2.0% w/v        sodium chloride and from about 0.1% to about 0.5% w/v potassium        chloride;    -   optionally, from about 0.1% to about 4% w/v of a polyol,        preferably the polyol is selected from 0.25% to about 4.0% w/v        of mannitol or glycerol;    -   optionally, from about 0.01% to about 2.0% w/v of a polyethylene        glycol selected from the group consisting of polyethylene glycol        400, polyethylene glycol 6000, polyethylene glycol 10000,        polyethylene glycol 20000 and a combination thereof;    -   optionally, from about 0.01 to about 4.0 mM menthol and/or from        about 0.1% to about 0.12% w/v sorbate;    -   optionally, from about 3 to about 10 millimolar of a citrate        buffer or a phosphate buffer wherein the concentration of the        viscosity enhancers provides a composition with a viscosity from        about 0.1 to about 1,000 centipoise (cps), preferably wherein a        low shear viscosity is from 1 to 1000 cps and a final high shear        viscosity is 30 cps or less.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   one or more nonionic surfactants selected from the group        consisting of polysorbate 80, poloxamer 407, poloxamer 188,        polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin at a        total concentration from about 0.1% to about 1.0% w/v or from        1.0% to about 5.9% w/v, wherein the upper range provides greater        tear moisture retention and therapeutic efficacy for more severe        dry eye;    -   from about 0.1% to about 2.0% w/v hydroxypropylmethyl cellulose        or a concentration of a cellulose derivative that yields a total        viscosity of the composition equal to the total viscosity of the        composition provided by from about 0.1% to about 1.5% w/v        hydroxypropylmethyl cellulose, preferably from about 0.1% to        about 1.35% w/v, including from about 0.9% to about 1.45% w/v of        carboxymethyl cellulose or carbomer 940;    -   from about 0.1% to about 2.0%% w/v sodium chloride, preferably        from about 0.25% to about 1.0% w/v;    -   from about 0.05% to about 0.1% w/v magnesium chloride;    -   optionally, from about 0.25% to about 4.0% w/v mannitol,        preferably from about 0.75% to about 2.5% w/v;    -   optionally, from about 0.1% to about 0.75% w/v polyethylene        glycol 400 or polyethylene glycol 20000;    -   optionally, from about 4 to about 8 millimolar citrate buffer or        phosphate buffer;    -   optionally, menthol, preferably from about 0.1 to about 1.75        millimolar, more preferably from about 1.0 to about 1.75        millimolar; and    -   optionally, sorbate, preferably at 0.1% or 0.12% w/v, wherein        optionally, the composition has a pH from about 5.0 to about        7.0.

In a preferred embodiment, the present invention is directed toartificial tear compositions comprising:

-   -   from about 2.0% to about 4.0% w/v of one or more nonionic        surfactants selected from the group consisting of polysorbates,        poloxamers, polyoxyl castor oils and combinations thereof;    -   from about 0.5% to about 2.0% w/v of a viscosity enhancer        selected from the group consisting of carboxymethyl cellulose        and carbomer 940;    -   from about 1.0% to about 5.0% w/v mannitol;    -   from about 0.5% to about 1.0% w/v of a polyethylene glycol        selected from polyethylene glycol 400, polyethylene glycol 6000,        polyethylene glycol 10000, polyethylene glycol 20000 and a        combination thereof;    -   from about 0.1% to about 2.0% w/v sodium chloride;    -   from about 0.1% to about 0.12% w/v sorbate;    -   from about 3.0 to about 10.0 millimolar citrate buffer,    -   wherein w/v denotes weight by total volume of the composition        and wherein the composition has a pH from about 5.0 to about        7.4, preferably from about 5.0 to about 6.0.

In another embodiment artificial tear compositions of the presentinvention, further comprising from about 0.25 to about 4.00 millimolarmenthol.

In another embodiment artificial tear compositions of the presentinvention, further comprising about 0.1% w/v magnesium chloride.

In another embodiment artificial tear compositions of the presentinvention, further comprising an excipient selected from the groupconsisting of about 0.1% w/v ethylenediaminetetraacetic acid, from about0.1% to about 0.5% w/v polyvinyl alcohol and a combination thereof.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   from about 0% to about 3.5% w/v polysorbate 80;    -   from about 0% to about 2.75% w/v poloxamer 407;    -   from about 0% to about 2.75% w/v poloxamer 188;    -   from about 0% to about 2.0% w/v polyoxyl castor oil;    -   from about 0.1% to about 2.0% w/v hydroxypropylmethyl cellulose;    -   from about 0% to about 2.0% w/v polyethylene glycol 400;    -   from about 0% to about 3.0% w/v mannitol;    -   from about 0% to about 0.90% w/v sodium chloride;    -   from about 0.04 to about 0.50 millimolar menthol;    -   about 4 millimolar citrate buffer; and    -   optionally, about 0.1% w/v sorbate,        wherein the composition has a pH of about 7.0 and wherein the        total nonionic surfactant concentration is from about 1.5% to        about 5.0% w/v.

In a more preferred embodiment, the present invention is directed toartificial tear compositions comprising:

-   -   a surfactant selected from the group consisting of about 3.50%        w/v poloxamer 407 or about 0.25% w/v poloxamer 407 and 1.75% w/v        sorbitol;    -   about 0.25% w/v polyoxyl 40 castor oil;    -   about 0.75% w/v of a polyethylene glycol having a molecular        weight from about 400 to about 20,000 Daltons;    -   about 1.00% w/v mannitol;    -   from about 0.45% to about 0.75% sodium chloride;    -   from about 0.90% to about 1.20% w/v carbomer 940;    -   from about 0.4 to about 2.75 millimolar menthol;    -   about 4.00 millimolar citrate buffer;    -   about 0.10% w/v ethylenediaminetetraacetic acid;    -   about 0.10% w/v polyvinyl alcohol; and    -   about 0.12% w/v sorbate.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   from about 0% to about 3.5% w/v polysorbate 80;    -   from about 0% to about 2.75% w/v poloxamer 407;    -   from about 0% to about 2.75% w/v poloxamer 188;    -   from about 0% to about 2.0% w/v polyoxyl castor oil;    -   from about 0.1% to about 2.0% w/v hydroxypropylmethyl cellulose;    -   from about 0% to about 2.0% w/v polyethylene glycol 400;    -   from about 0% to about 3.0% w/v mannitol;    -   from about 0% to about 0.90% w/v sodium chloride;    -   from about 0.04 to about 0.50 millimolar menthol;    -   about 4 millimolar citrate buffer; and    -   optionally, about 0.1% w/v sorbate,        wherein the composition has a pH of about 7.0 and wherein the        total nonionic surfactant concentration is from about 1.5% to        about 5.0% w/v.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   two or more nonionic surfactants selected from the group        consisting of polysorbate 80, poloxamer 407, poloxamer 188,        polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin at a        total concentration from about 1.5% to about 5.9% w/v;    -   about 1% w/v mannitol;    -   about 0.1% w/v hydroxypropylmethyl cellulose or a concentration        of carboxymethyl cellulose that yields a total viscosity of the        composition equal to the total viscosity of the composition        provided by about 0.1% w/v hydroxypropylmethyl cellulose;    -   from about 0.1% to about 0.75% w/v sodium chloride, preferably        from about 0.3% to about 0.4% w/v;    -   about 0.1% w/v magnesium chloride;    -   optionally, about 3 millimolar phosphate buffer or for pH less        than 6.0 citrate buffer;    -   optionally, from about 0.1 to about 0.50 millimolar menthol; and    -   optionally, about 0.1% w/v sorbate,        wherein optionally, the composition has a pH from about 5.0 to        about 7.0.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   two or more nonionic surfactants selected from the group        consisting of polysorbate 80, poloxamer 407, poloxamer 188,        polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin at a        total concentration from about 1.5% to about 5.9% w/v;    -   from about 1.0% to 2.5% w/v mannitol;    -   from about 0.10% to about 1.5% w/v hydroxypropylmethyl cellulose        or a concentration of carboxymethyl cellulose that yields a        total viscosity of the composition equal to the total viscosity        of the composition provided by from about 0.1% to about 1.5% w/v        hydroxypropylmethyl cellulose;    -   from about 0.1% to about 0.5% w/v sodium chloride, preferably        from about 0.2% to about 0.4% w/v;    -   about 0.1% w/v magnesium chloride;    -   optionally, about 3 millimolar phosphate or citrate buffer;    -   optionally, from about 0.1 to about 0.50 millimolar menthol;    -   optionally, about 0.1% w/v sorbate,        wherein optionally, the composition has a pH from about 5.0 to        about 7.0.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   two or more nonionic surfactants selected from the group        consisting of polysorbate 80, poloxamer 407, poloxamer 188,        polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin at a        total concentration from about 1.5% to about 5.9% w/v;    -   about 2.5% w/v mannitol;    -   from about 0.65% to about 1.0% w/v hydroxypropylmethyl cellulose        or a concentration of carboxymethyl cellulose that yields a        total viscosity of the composition equal to the total viscosity        of the composition provided by from about 0.65% to about 1.0%        w/v hydroxypropylmethyl cellulose;    -   from about 0.1% to about 0.75% w/v sodium chloride, preferably        from about 0.3% to about 0.4% w/v;    -   about 0.1% w/v magnesium chloride;    -   optionally, about 3 millimolar phosphate buffer or about 4        millimolar citrate buffer;    -   optionally, from about 0.1 to about 0.50 millimolar menthol;    -   optionally, about 0.1% w/v sorbate,        wherein optionally, the composition has a pH from about 5.5 to        about 7.0.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   two or more nonionic surfactants selected from the group        consisting of polysorbate 80, poloxamer 407, poloxamer 188,        polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin at a        total concentration from about 1.5% to about 5.9% w/v;    -   about 2.5% w/v mannitol;    -   from about 1.0% to about 1.35% w/v hydroxypropylmethyl cellulose        or a concentration of carboxymethyl cellulose that yields a        total viscosity of the composition equal to the total viscosity        of the composition provided by from about 1.0% to about 1.35%        w/v hydroxypropylmethyl cellulose;    -   from about 0.1% to about 0.75% w/v sodium chloride, preferably        from about 0.3% to about 0.4% w/v;    -   about 0.1% w/v magnesium chloride;    -   optionally, about 3 millimolar phosphate buffer or about 4        millimolar citrate buffer;    -   optionally, from about 0.1 to about 0.50 millimolar menthol;    -   optionally, about 0.1% w/v sorbate,        wherein optionally, the composition has a pH from about 5.5 to        about 7.0.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   two or more nonionic surfactants selected from the group        consisting of polysorbate 80, poloxamer 407, poloxamer 188,        polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin at a        total concentration from about 1.0% to about 5.9% w/v;    -   about 2.5% w/v mannitol;    -   from about 1.35% to about 1.45% w/v hydroxypropylmethyl        cellulose or a concentration of carboxymethyl cellulose that        yields a total viscosity of the composition equal to the total        viscosity of the composition provided by from about 1.35% to        about 1.45% w/v hydroxypropylmethyl cellulose;    -   from about 0.1% to about 0.75% w/v sodium chloride, preferably        from about 0.3% to about 0.4% w/v;    -   about 0.1% w/v magnesium chloride;    -   optionally, about 3 millimolar phosphate buffer or about 4        millimolar citrate buffer;    -   optionally, from about 0.1 to about 0.50 millimolar menthol;    -   optionally, about 0.1% w/v sorbate,        wherein optionally, the composition has a pH from about 5.5 to        about 7.0.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   two or more nonionic surfactants selected from the group        consisting of polysorbate 80, poloxamer 407, poloxamer 188,        polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin at a        total concentration from about 1.5% to about 5.9% w/v, wherein        one of the two or more nonionic surfactants is from about 0.25%        to about 1.0% w/v polyoxyl castor oil;    -   about 2.5% w/v mannitol;    -   from about 1.25% to about 1.35% w/v hydroxypropylmethyl        cellulose or a concentration of carboxymethyl cellulose that        yields a total viscosity of the composition equal to the total        viscosity of the composition provided by from about 1.25% to        about 1.35% w/v hydroxypropylmethyl cellulose;    -   from about 0.1% to about 0.75% w/v sodium chloride, preferably        from about 0.3% to about 0.4% w/v;    -   about 0.1% w/v magnesium chloride;    -   optionally, about 3 millimolar phosphate or citrate buffer;    -   optionally, from about 0.1 to about 0.50 millimolar menthol;    -   optionally, about 0.1% w/v sorbate,        wherein optionally, the composition has a pH from about 5.0 to        about 7.0.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   about 2.0% w/v polysorbate 80;    -   about 0.2% w/v poloxamer 407;    -   about 0.5% w/v poloxamer 188;    -   about 1.0% w/v hydroxypropyl-gamma-cyclodextrin;    -   from about 0.5% to about 1.25% w/v hydroxypropylmethyl cellulose        or a concentration of a cellulose derivative that yields a total        viscosity of the composition equal to the total viscosity of the        composition provided by from about 0.5% to about 1.25% w/v        hydroxypropylmethyl cellulose;    -   from about 0.20% to about 0.75% w/v sodium chloride;    -   about 0.1% w/v magnesium chloride; and    -   about 0.025 to about 0.07 millimolar menthol.

The present invention is further directed to an artificial tearcomposition for severe dry eye comprising:

-   -   about 2.0% w/v polysorbate 80;    -   about 0.2% w/v poloxamer 407;    -   about 0.5% w/v poloxamer 188;    -   about 1.0% w/v hydroxypropyl-gamma-cyclodextrin;    -   from about 1.25% to about 1.35% w/v hydroxypropylmethyl        cellulose or a concentration of a cellulose derivative that        yields a total viscosity of the composition equal to the total        viscosity of the composition provided by from about 1.25% to        about 1.35% w/v hydroxypropylmethyl cellulose;    -   from about 0.25% to about 0.75% w/v sodium chloride;    -   about 0.1% w/v magnesium chloride; and    -   about 0.07 to about 0.1 millimolar menthol.

The present invention is further directed to an artificial tearcomposition for severe dry eye comprising:

-   -   about 2.0% w/v polysorbate 80;    -   about 0.2% w/v poloxamer 407;    -   about 0.5% w/v poloxamer 188;    -   about 1.0% w/v hydroxypropyl-gamma-cyclodextrin;    -   from about 1.35% to about 1.5% w/v hydroxypropylmethyl cellulose        or a concentration of a cellulose derivative that yields a total        viscosity of the composition equal to the total viscosity of the        composition provided by from about 1.35% to about 1.5% w/v        hydroxypropylmethyl cellulose;    -   from about 0.25% to about 0.75% w/v sodium chloride;    -   about 0.1% w/v magnesium chloride; and    -   about 0.1 to about 0.20 millimolar menthol.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   about 3.5% w/v polysorbate 80;    -   about 0.7% w/v poloxamer 407;    -   about 1.0% w/v poloxamer 188;    -   about 0.01% w/v polyoxyl castor oil;    -   about 0.85% w/v hydroxypropylmethyl cellulose;    -   about 2.5% w/v mannitol;    -   about 0.1% w/v magnesium chloride;    -   about 0.25% w/v sodium chloride;    -   from about 0.07 to about 0.50 millimolar menthol, preferably        0.07, 0.10, 0.14 0.20 or 0.40 millimolar menthol;    -   optionally, about 0.1% w/v sorbate; and    -   about 3 millimolar phosphate buffer or about 4 millimolar        citrate buffer,        wherein the composition has a pH of about 7.0.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   about 3.5% w/v polysorbate 80;    -   about 0.2% w/v poloxamer 407;    -   about 0.2% w/v poloxamer 188;    -   about 0.01% w/v polyoxyl castor oil;    -   about 0.70% to about 0.80% w/v hydroxypropylmethyl cellulose,        preferably 0.70%, 0.75% or 0.80% w/v;    -   about 2.5% w/v mannitol;    -   about 0.1% w/v magnesium chloride;    -   about 0.25% to about 0.35% w/v sodium chloride, preferably        0.25%, 0.30% or 0.35% w/v;    -   from about 0.07 to about 0.14 millimolar menthol, preferably        0.07, 0.10, or millimolar menthol;    -   optionally, about 0.1% w/v sorbate; and    -   about 3 millimolar phosphate buffer or about 4 millimolar        citrate buffer,        wherein the composition has a pH of about 7.0.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   about 2.0% w/v polysorbate 80;    -   about 0.2% w/v poloxamer 407;    -   about 0.5% w/v poloxamer 188;    -   about 1.0% w/v hydroxypropyl-gamma-cyclodextrin;    -   from about 0.5% to about 1.25% w/v hydroxypropylmethyl cellulose        or a concentration of a cellulose derivative that yields a total        viscosity of the composition equal to the total viscosity of the        composition provided by from about 0.5% to about 1.25% w/v        hydroxypropylmethyl cellulose;    -   from about 0.2% to about 0.75% w/v sodium chloride;    -   about 0.1% w/v magnesium chloride; and    -   about 0.025 to about 0.07 millimolar menthol.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   about 2.0% w/v polysorbate 80;    -   about 0.2% w/v poloxamer 407;    -   about 0.5% w/v poloxamer 188;    -   about 1.0% w/v hydroxypropyl-gamma-cyclodextrin;    -   from about 1.25% to about 1.35% w/v hydroxypropylmethyl        cellulose or a concentration of a cellulose derivative that        yields a total viscosity of the composition equal to the total        viscosity of the composition provided by from about 1.25% to        about 1.35% w/v hydroxypropylmethyl cellulose;    -   from about 0.25% to about 0.75% w/v sodium chloride;    -   about 0.1% w/v magnesium chloride; and    -   about 0.07 to about 0.1 millimolar menthol.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   about 3.0% w/v polysorbate;    -   about 0.10% w/v poloxamer 188;    -   about 0.01% w/v polyoxyl castor oil;    -   from about 0.0% to about 2.0% w/v hydroxypropylmethyl cellulose;    -   from about 0.5% to about 2.5% w/v mannitol;    -   about 0.10% w/v magnesium ions;    -   from about 0.0% to about 0.75% w/v NaCl; and    -   a buffer at a concentration from about 1 mM to about 100 mM,        wherein the composition has a pH from about 5.5 to about 8.0 and        wherein the viscosity is less than or equal to 500 centipoise.

The present invention is further directed to an artificial tearcomposition comprising:

-   -   about 4.0% w/v Captisol®;    -   about 1.35% w/v HPMC;    -   about 0.02% w/v BAK;    -   about 0.10% w/v sorbate;    -   about 0.10% w/v EDTA;    -   about 3 mM Citrate buffer; and    -   from about 0.3% to about 0.5% w/v NaCl,        wherein the composition has a pH from about 6.0.

TABLE 1 Artificial Tear Compositions (% w/v) A B C D E F G H Polysorbate80 3.00% 3.00% 3.00% 3.00% 2.50% 1.50% 1.50% 3.00% Poloxamer 407 — — — —0.20% 0.20% 0.20% — Poloxamer 188 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%0.10% — Polyoxyl castor oil 0.01% 0.01% 0.01% 0.01% — — — 0.01%Hydroxypropyl-gamma- — — — — 1.00% 2.00% 1.00% — cyclodextrin Mannitol2.50% 2.50% 2.50% 2.50% 2.50% 2.50% 2.50% 2.50% HPMC 0.10% 0.65% 1.00%1.35% 1.30% 1.40% 1.45% 1.25% NaCl 0.20% 0.75% 0.75% 0.75% 0.30% 0.40%0.35% 0.30% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%Menthol (mM) — — — — 0.07 0.1 0.1 — Phosphate buffer or 3 3 3 3 3 3 3 3Citrate buffer (mM) pH 7.0 7.0 7.0 7.0 5.5 5.5 5.5 — (% w/v) I J K L M NO P Polysorbate 80 1.50% 1.50% 1.50% 3.00% 1.50% 1.50% 3.50% 1.50%Poloxamer 407 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% 0.70% 0.20% Poloxamer188 1.00% 1.00% 0.50% 0.10% 0.75% 0.75% 1.00% 0.50% Polyoxyl castor oil0.01% 0.01% 1.00% 0.01% 0.01% 0.01% 0.01% 1.00% Hydroxypropyl-gamma-0.50% 0.50% 0.50% 0.50% 1.50% 1.50% — 0.50% cyclodextrin Mannitol 2.50%2.50% 2.50% 1.00% 2.50% 2.50% 2.50% 2.50% HPMC 1.25% 1.35% 1.35% 0.10%1.35% 1.45% 0.85% 1.25% NaCl 0.30% 0.30% 0.30% 0.30% 0.40% 0.25% 0.25%0.30% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% Menthol (mM)— — — — 0.15 0.15-0.25 0.07-0.20 — Phosphate buffer or 3 3 3 3 3 3 3 3Citrate buffer (mM) pH — — — 7.0 5.5 5.5 7 — (% w/v) Q R S T U V WPolysorbate 80 1.00% 3.00% 1.00% 1.50% 1.50% 2.00% 3.00% Poloxamer 4070.20% — 0.20% 0.20% 0.20% 0.20% 0.20% Poloxamer 188 0.10% — 0.10% 0.10%0.10% 0.50% 0.20% Polyoxyl castor oil — — — — — — 0.01%Hydroxypropyl-gamma- — — 0.50% 1.00% 1.00% 1.00% — cyclodextrin Mannitol1.00% 1.00% 1.00% 2.50% 2.50% — 1.00% HPMC 0.10% 0.10% 0.10% 1.30% 1.40%— 0.10% NaCl 0.40% 0.40% 0.40% 0.30% 0.30% 0.75% 0.30% MgCl₂ 0.10% 0.10%0.10% 0.10% 0.10% 0.10% 0.10% Menthol (mM) — — — 0.07 0.1 0.1-0.2 —Phosphate buffer or 3 3 3 3 3 3 3 Citrate buffer (mM) pH — — — 5.5 5.5 —7.0

TABLE 2 More Artificial Tear Compositions (% w/v) 1 2 3 4 5 6 7 8 9Polyoxyl 40 4.50% 5.00% 5.50% 5.00% 5.00% 5.00% 5.00% 5.00% 5.00%stearate Poloxamer 407 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% 0.20%Poloxamer 188 0.10% 0.10% 0.10% 0.10% Polysorbate 80 Polysorbate 20Polyoxyl 35 castor oil CMC 0.55% 0.55% 0.55% 0.55% 0.55% 0.25% HPC HPMC0.40% 0.62% 0.55% 0.25% Glycerin NaCl 0.25% ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ BAK 0.01%✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Visual Blur 30-60 30-60 30-60 30-60 10 20-30 30-60 10(sec) (% w/v) 10 11 12 13 14 15 16 17 18 Polyoxyl 40 5.00% 5.00% 5.00%5.00% 5.00% 5.00% 3.70% 3.70% 4.75% stearate Poloxamer 407 0.20% 0.20%0.20% 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% Poloxamer 188 0.10% 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% Polysorbate 80 1.00% 1.00%1.00% 1.00% 1.00% 1.00% Polysorbate 20 0.05% Polyoxyl 35 castor oil CMC0.25% 0.55% 0.75% 0.62% HPC 1.25% 1.75% 1.40% HPMC 0.25% 0.55% 0.75%Glycerin NaCl 0.25% ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ BAK 0.01% ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ VisualBlur 10 30-40 90-180 60-90 5 30 10-20 (sec) (% w/v) 19 20 21 22 23 24 2526 27 Polyoxyl 40 5.00% 5.00% 5.00% 5.00% 5.00% 5.00% 5.00% stearatePoloxamer 407 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% Poloxamer188 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% Polysorbate 80 5.00%Polysorbate 20 Polyoxyl 35 castor oil CMC 0.50% 0.75% HPC 1.50% HPMC0.30% 0.30% 0.50% 0.10% 0.20% 0.30% Glycerin NaCl 0.25% ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓✓ BAK 0.01% ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Visual Blur 45 2 5 20 30 15 3.5 5 5Wetting Effect 90 30 30 60 90 45 45 45 45 (min) Comfort 3.5 3.5 3.0 3.53.5 3.5 3.5 3.5 3.5 (4 is best) Visual Quality 3.7 3.7 3.5 3.5 3.5 3.83.7 3.8 3.8 (4 is best) Overall 2.0 3.0 3.0 3.0 3.1 3.1 3.2 3.2 3.2Performance (% w/v) 28 29 30 31 32 33 34 35 Polyoxyl 40 5.00% 5.00%5.00% 5.00% stearate Poloxamer 407 0.20% 5.00% 0.20% 0.20% 5.00% 0.20%0.20% 0.20% Poloxamer 188 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%Polysorbate 80 1.00% Polysorbate 20 Polyoxyl 35 0.25% 1.00% 1.50% castoroil CMC 0.50% 0.50% HPC 1.75% 1.00% HPMC 0.30% 0.30% 0.30% 0.30%Glycerin 0.30% NaCl 0.25% ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ BAK 0.01% ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓Visual Blur 45 40 7 15 20 0 1 1 Wetting Effect 30 60 45 60 60 90 180 180(min) Comfort 3.0 3.5 3.7 3.5 3.5 4.0 4.0 4.0 (4 is best) Visual Quality3.5 3.5 3.5 3.5 3.5 3.9 4.0 4.0 (4 is best) Overall 3.2 3.2 3.5 3.5 3.53.8 4.0 4.0 Performance (% w/v) 36 37 38 39 40 41 42 43 44 45 46Polysorbate 80 3.00% 3.00% 3.00% 3.00% 3.00% 3.00% 3.00% 3.00% 3.00%3.00% 3.00% Poloxamer 188 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% Polyoxyl 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%0.01% 0.01% 0.01% 0.01% 0.01% Castor oil Mannitol 1.00% 1.00% 1.00%1.00% 2.50% 2.50% 2.50% 2.50% 2.50% 2.50% 2.50% HPMC 0.10% 0.10% 0.10%0.10% 0.50% 0.50% 0.50% 0.50% 0.50% 0.65% 0.75% NaCl 0.20% 0.25% 0.50%0.75% 0.00% 0.20% 0.50% 0.50% 0.75% 0.20% 0.00% MgCl₂ 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% Glycerin 0.00% 0.00%0.00% 0.00% 0.00% 0.00% 0.00% 1.00% 0.00% 0.00% 0.00% Phosphate 3.003.00 3.00 3.00 3.00 2.00 2.00 2.00 2.00 3.00 3.00 buffer mM pH 7.00 7.007.00 7.00 7.00 7.00 7.00 7.00 7.00 7.00 7.00 Osmolarity 284 369 32 39 10(d) (mOsm) Shear Rate 10-1000 10-1000 10-1000 10-1000 10-1000 Viscosity72 100 100 110 147 (cps) (% w/v) 47 48 49 50 51 52 53 54 55 56 57Polysorbate 80 3.00% 3.00% 3.00% 3.00% 3.00% 3.00% 5.00% 7.00% 3.00%3.00% 3.00% Poloxamer 188 0.01% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% Polyoxyl 0.01% 0.00% 0.0001% 0.001% 0.01% 0.01%0.01% 0.01% 0.01% 0.01% 0.01% Castor oil Mannitol 2.50% 2.50% 2.50%2.50% 2.50% 2.50% 2.50% 2.50% 2.50% 2.50% 2.50% HPMC 0.75% 1.00% 1.00%1.00% 1.00% 1.00% 1.00% 1.00% 1.35% 1.48% 1.48% NaCl 0.20% 0.00% 0.00%0.00% 0.00% 0.20% 0.20% 0.20% 0.50% 0.50% 0.70% MgCl₂ 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% Glycerin 0.00% 0.00%0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% Phosphate 3.003.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00 buffer mM pH 7.00 7.007.00 7.00 7.00 7.00 7.00 7.00 7.00 7.00 7.00 Osmolarity 15 (d) 15 (d) 12(d) 12 (d) 16 (d) (mOsm) Shear Rate 10-1000 10-1000 10-1000 10-100010-1000 Viscosity 164 214 181 233 192 (cps) (d) denotes diluted tentimes

AQus™ CL-Tears may represent compositions with the following ingredientsand concentrations:

-   -   3.0% polysorbate 80    -   0.10% poloxamer 188    -   0.01% polyoxyl castor oil    -   0.50% HPMC    -   0.5% to 2.5% mannitol (1.0% preferred)    -   0.10% MgCl₂    -   0.1% to 0.75% NaCl, preferably 0.2% to 0.5%    -   optionally 1.0% glycerin    -   2-3 mM phosphate buffer    -   pH 7.0

AQus™ CL-Tears may also represent compositions with the followingingredients and concentrations:

-   -   0.0% to 1.5% polysorbate 80    -   0.10% poloxamer 188    -   0.01% polyoxyl castor oil    -   1.5% to 3.0% hydroxy propyl gamma cyclodextrin    -   0.50% HPMC    -   0% to 2.5% mannitol (1.0% preferred)    -   0% to 0.10% MgCl₂    -   0.1% to 0.75% NaCl, preferably 0.2% to 0.5%    -   optionally 1.0% glycerin    -   2-3 mM phosphate buffer    -   pH 7.0

AQus™ CL-Tears may also represent compositions may represent compositionof Table 3.

TABLE 3 AQus ™ CL-Tears Compositions (% w/v) 58 59 60 61 62 63 64 65 66Polysorbate 80 3.00% 3.00% 3.00% 2.50% 2.00% 1.50% 1.50% 1.50% 1.00%Poloxamer 407 — 0.20% 0.20% 0.10% 0.20% 0.20% 0.20% 0.20% 0.20%Poloxamer 188 0.10% 0.10% 0.10% 1.00% 0.50% 1.00% 0.10% 1.00% 0.10%Polyoxyl Castor oil 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%0.01% Hydroxypropyl-gamma- — — 0.50% 0.25% 1.00% 0.50% 1.50% 1.00% 1.50%cyclodextrin HPMC 0.10% 0.10% 0.10% 0.10% 0.10% — — 0.10% — CMC (% HPMCequivalent) — — — — — 0.10% 0.10% 0.10% PEG 400 — — — 0.50% 0.25% — — —Mannitol 1.00% 1.00% 1.00% 2.50% 1.00% — 1.00% 1.00% — MgCl₂ 0.10% 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% NaCl* 0.30% 0.30% 0.30% 0.30%0.30% 0.40% 0.40% 0.40% 0.30% Phosphate buffer (mM) 3.00 3.00 3.00 3.003.00 3.00 3.00 3.00 3.00 pH 7.00 7.00 7.00 7.00 7.00 7.00 7.00 7.00 7.00Menthol (mM) — — — — — — — — — viscosity (cps) 2.00 2.00 2.00 >100 2.002.00 2.00 2.00 2.00 (% w/v) 67 68 69 70 71 72 73 74 75 Polysorbate 801.00% 1.00% 1.00% 1.00% 1.00% 1.00% 0.50% 0.50% 1.50% Poloxamer 4070.20% 0.20% 0.20% 1.00% 1.00% 1.00% — — 0.20% Poloxamer 188 0.10% 0.50%1.00% 1.00% 1.00% 1.00% 0.10% 0.10% 0.10% Polyoxyl Castor oil 0.50%0.10% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 1.00% Hydroxypropyl-gamma-1.50% 1.50% 1.50% — — — 2.50% 3.00% 0.50% cyclodextrin HPMC 0.10% 0.10%— 0.10% — 0.10% 0.10% 0.10% — CMC (% HPMC equivalent) 0.10% — 0.10% — —— — PEG 400 — — — — — — — — 1.00% Mannitol — — — 1.00% 1.00% 1.00% 1.00%1.00% — MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%NaCl* 0.30% 0.30% 0.30% 0.30% 0.40% 0.40% 0.40% 0.40% 0.40% Phosphatebuffer (mM) 3.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00 pH 7.00 7.007.00 7.00 7.00 7.00 7.00 7.00 7.0 Menthol (mM) 0.05 — — — — — — — —viscosity (cps) 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 (% w/v) 7677 78 79 80 81 82 83 84 Polysorbate 80 1.00% 1.00% 2.00% 2.00% 2.00%2.00% 2.00% 2.00% 2.00% Poloxamer 407 0.50% 0.50% 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% Poloxamer 188 1.00% 1.00% 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% Polyoxyl Castor oil 0.01% 0.01% 0.01% 0.01%0.01% 0.01% 0.01% 0.01% 0.01% HPMC 0.50% 0.50% 0.50% 0.20% 0.50% 0.50%0.50% 0.50% 0.50% PEG 400 0.25% 0.25% 0.25% 0.20% 0.25% 0.25% 0.25%0.25% 0.25% Mannitol 0.25% 0.25% 0.25% 0.20% 0.25% 1.00% 0.25% 0.50%0.50% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% NaCl*0.30% 0.30% 0.25% 0.25% 0.25% 0.35% 0.25% 0.40% 0.40% Citrate buffer(mM) 4.00 4.00 4.00 — — — — — — pH 7.00 7.00 7.00 7.00 7.00 7.00 7.007.00 7.00 Menthol (mM) 0.04 0.04 0.02 0.02 — 0.08 0.08 0.12 0.13 Sorbate— 0.1% 0.1% 0.1% — — — — — (% w/v) 85 86 87 88 89 90 91 92 93Polysorbate 80 2.00% 2.00% 2.00% 2.00% 2.00% 2.00% 2.00% 2.00% 2.00%Poloxamer 407 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%Poloxamer 188 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%Polyoxyl Castor oil 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%0.01% HPMC 0.50% 0.50% 0.50% 0.20% 0.50% 0.50% 0.50% 0.50% 0.50% PEG 4000.25% 0.25% 0.25% 0.20% 0.25% 0.25% 0.25% 0.25% 0.25% Mannitol 0.50%0.50% 0.50% 0.20% 0.25% 1.00% 0.25% 0.50% 0.50% MgCl₂ 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.10% NaCl* 0.40% 0.40% 0.40% 0.25% 0.25%0.25% 0.25% 0.40% 0.40% Citrate buffer (mM) — — — 4.00 4.00 4.00 4.004.00 4.00 pH 7.00 7.00 7.00 7.00 7.00 7.00 7.00 7.00 7.00 Menthol (mM)0.14 0.15 0.16 — — 0.08 0.08 0.12 0.13 Sorbate — — — 0.1 0.1 0.1 0.1 0.10.1 EDTA — — — 0.1 0.1 0.1 0.1 0.1 0.1 (% w/v) 94 95 96 Polysorbate 802.00% 2.00% 2.00% Poloxamer 407 0.10% 0.10% 0.10% Poloxamer 188 0.10%0.10% 0.10% Polyoxyl Castor oil 0.01% 0.01% 0.01% HPMC 0.50% 0.50% 0.50%PEG 400 0.25% 0.25% 0.25% Mannitol 0.50% 0.50% 0.50% MgCl₂ 0.10% 0.10%0.10% NaCl* 0.40% 0.40% 0.40% Citrate buffer (mM) 4.00 4.00 4.00 pH 7.007.00 7.00 Menthol (mM) 0.14 0.15 0.16 Sorbate 0.1 0.1 0.1 EDTA 0.1 0.10.1 *NaCl may be at a concentration from 0.1% to 0.75%, preferably from0.2% to 0.5% “% HPMC equivalent” denotes an amount of CMC necessary toresult in a final viscosity equivalent to the final viscosity achievedif the given % w/v of HPMC were used.

AQus™ Tears Plus may represent compositions of Table 4.

TABLE 4 AQus ™ Tears Plus Compositions (% w/v) 97 98 99 100 101 102 103104 Polysorbate 80 3.50% 3.00% 3.00% 3.00% 2.75% 2.00% 2.00% 1.50%Poloxamer 407 0.20% 0.10% 0.10% — 0.20% 0.20% 0.20% 0.20% Poloxamer 1880.10% 0.50% 0.10% — 0.10% 0.50% 0.10% 0.75% Polyoxyl Castor oil 0.01%0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% Hydroxypropyl-gamma- — 0.25%0.70% — 0.75% 1.00% 1.50% 1.50% cyclodextrin HPMC 0.85% 1.25% 1.00%0.65% 1.00% 1.25% 1.25% 1.00% CMC (% HPMC equivalent) — — — — — — — —PEG 400 — 0.25% — — — — — — Mannitol 2.50% 2.50% 2.50% 2.50% 2.50% 2.50%2.50% 2.50% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% NaCl*0.25% 0.30% 0.30% 0.30% 0.40% 0.25% 0.30% 0.30% Phosphate buffer (mM)3.00 3.00 — 3.00 3.00 — — — Citrate buffer (mM) — — 3.00 — — 3.00 3.003.00 pH 7.00 7.00 5.50 7.00 7.00 5.50 6.00 5.50 Menthol (mM) 0.07 0.120.07 — 0.15 0.17 0.15 0.15 Sorbate — — 0.10% — — — — — (% w/v) 105 106107 108 109 110 111 112 Polysorbate 80 1.50% 1.50% 1.00% 1.00% 0.50%0.50% 0.50% 0.50% Poloxamer 407 0.20% 0.20% 1.00% — — — — — Poloxamer188 0.50% 0.10% 1.00% 0.10% 0.10% 0.10% 0.10% 0.10% Polyoxyl Castor oil0.01% 0.01% 0.01% — 0.01% 0.01% 0.01% 0.01% Hydroxypropyl-gamma- 1.50%1.50% — 2.00% 3.00% 3.00% 3.00% 3.00% cyclodextrin HPMC 1.35% — 0.65%0.75% 0.75% — 0.75% 0.75% CMC (% HPMC equivalent) — 1.00% — — — 0.75% —— PEG 400 — — — — — — — — Mannitol 1.00% 2.50% 2.50% 2.50% 2.50% 2.50%2.50% 2.50% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% NaCl*0.40% 0.30% 0.30% 0.40% 0.40% 0.40% 0.40% 0.40% Phosphate buffer (mM)3.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00 Citrate buffer (mM) — — — — — —— — pH 7.00 6.00 7.00 7.00 6.00 6.00 6.00 6.00 Menthol (mM) 0.12 0.10 —— 0.10 0.10 — — Sorbate — — — — — — 0.10% — (% w/v) 113 114 115 115B115C 115D 115E Polysorbate 80 1.5% 1.5% 3.0% 1.00% 1.00% 1.00% 1.00%Poloxamer 407 0.7% 0.7% 0.1% 0.50% 0.50% 1.00% 1.00% Poloxamer 188 1.0%1.0% 0.1% 1.00% 1.00% 0.20% 0.20% Polyoxyl Castor oil 0.01% 0.01% 0.01%0.01% 0.01% 0.01% 0.01% Hydroxypropyl-gamma- — — — — — 1.50% 1.50%cyclodextrin HPMC 0.95% 0.95% 0.95% 0.50% 0.50% 0.20% 0.20% CMC (% HPMCequivalent) — — — — — — — PEG 400 1.0% 1.0% 2.0% 0.25% 0.25% 0.50% 0.50%Mannitol 0.5% 0.5% 0.5% 0.25% 0.25% 1.00% 1.00% MgCl₂ 0.1% 0.1% 0.1%0.10% 0.10% 0.10% 0.10% NaCl* 0.35% 0.35% 0.4% 0.30% 0.30% 0.35% 0.4%Phosphate buffer (mM) — — — — — 3.00 3.00 Citrate buffer (mM) 4.00 4.004.00 4.00 4.00 — — pH 7 7 7 7.00 7.00 7.0 7.0 Menthol (mM) 0.09 0.090.09 0.02 0.02 0.10 0.01 Sorbate — 0.1% 0.1% — 0.1% — — *NaCl may be ata concentration from 0.1% to 0.75%, preferably from 0.2% to 0.5% “% HPMCequivalent” denotes an amount of CMC necessary to result in a finalviscosity equivalent to the final viscosity achieved if the given % w/vof HPMC were used

AQus™ Tears Advanced may represent compositions of Table 5.

TABLE 5 AQus ™ Tears Advanced Compositions (% w/v) 116 117 118 119 120121 122 123 Polysorbate 80 3.50% 3.00% 2.75% 2.00% 1.50% 1.50% 1.50%1.50% Poloxamer 407 0.20% 0.10% 0.20% 0.20% 0.20% 0.20% 0.20% 0.20%Poloxamer 188 0.10% 0.10% 0.10% 0.10% 0.75% 0.50% 0.50% 0.10% PolyoxylCastor oil 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%Hydroxypropyl-gamma- — 0.70% 0.75% 1.50% 1.50% 1.50% 1.50% 2.00%cyclodextrin HPMC 1.25% 1.40% 1.25% 1.30% 1.35% 1.35% 1.35% 1.35% CMC (%HPMC equivalent) — — — — — — — — PEG 400 — — — — — 0.25% — — Mannitol2.50% 2.50% 2.50% 2.50% 2.50% 2.50% 2.50% 2.50% MgCl₂ 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% 0.10% NaCl* 0.25% 0.30% 0.25% 0.30% 0.40% 0.40%0.40% 0.25% Citrate Buffer (mM) 3.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00pH 5.50 5.00 5.50 5.50 5.50 5.50 5.50 5.00 Menthol (mM) 0.15 0.20 0.150.17 0.15 0.17 0.15 0.17 Sorbate — — — — — — 0.10% — (% w/v) 124 125 126127 128 129 130 Polysorbate 80 0.50% 0.50% 0.50% 0.50% 0.50% 2.00% 0.50%Poloxamer 407 — — — — — 0.20% — Poloxamer 188 — 0.10% 0.10% 0.10% 0.10%0.10% 0.10% Polyoxyl Castor oil — 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%Hydroxypropyl-gamma- 3.50% 3.50% 4.00% 4.00% 4.00% 1.50% 4.00%cyclodextrin HPMC 1.00% 1.00% 1.25% — 1.25% — 1.25% CMC (% HPMCequivalent) — — — 1.25% — 1.30% — Mannitol 2.50% 2.50% 2.50% 2.50% 2.50%2.50% 2.50% PEG 400 — — — — — — — MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10%0.10% 0.10% NaCl* 0.30% 0.40% 0.40% 0.40% 0.40% 0.30% 0.40% CitrateBuffer (mM) 3.00 3.00 3.00 3.00 3.00 3.00 3.00 pH 6.00 7.00 5.50 5.505.50 5.50 5.50 Menthol (mM) — — 0.10 0.10 — 0.10 — Sorbate — — — — 0.10%0.10% — (% w/v) 131B 131C 131D 131E 131F 131G Polysorbate 80 1.00% 1.00%1.00% 1.00% 1.00% 1.00% Poloxamer 407 0.50% 0.50% 0.50% 0.50% 1.00%1.00% Poloxamer 188 1.00% 1.00% 1.00% 1.00% 0.20% 0.20% Polyoxyl Castoroil 0.01% 0.01% 0.5% 0.5% 0.01% 0.25% Hydroxypropyl-gamma- — — — — 1.50%1.50% cyclodextrin HPMC 0.50% 0.50% 0.85% 0.85% 0.75% 1.00% Mannitol0.25% 0.25% 0.25% 0.25% 1.00% 1.00% PEG 400 0.25% 0.25% 0.25% 0.25%0.50% 0.50% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% NaCl* 0.30% 0.30%0.30% 0.30% 0.35% 0.35% Phosphate Buffer (mM) — — — — 4.00 4.00 CitrateBuffer (mM) 4.00 4.00 4.00 4.00 — — pH 7.00 7.00 7.00 7.00 6.0 6.2Menthol (mM) 0.04 0.04 0.06 0.06 0.30 0.27 Sorbate — 0.10% — 0.10% 0.11%0.10% *NaCl may be at a concentration from 0.1% to 0.75%, preferablyfrom 0.2% to 0.5% “% HPMC equivalent” denotes an amount of CMC necessaryto result in a final viscosity equivalent to the final viscosityachieved if the given % w/v of HPMC were usedequivalent to the final viscosity achieved if the given % w/v of HPMCwere used

AQus™ Tears Advanced Plus or AQus™ Tears Extreme may representcompositions of Table 6.

TABLE 6 AQus ™ Tears Advanced Plus and AQus ™ Tears Extreme Compositions(% w/v) 131 132 133 134 135 136 137 138 Polysorbate 80 3.50% 2.75% 2.00%2.00% 1.50% 1.50% 0.50% 0.50% Poloxamer 407 0.20% 0.20% 0.20% 0.20%0.20% 0.20% — — Poloxamer 188 0.10% 0.10% 0.10% 0.10% 0.75% 0.10% 0.40%0.40% Polyoxyl Castor oil 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%0.01% Hydroxypropyl-gamma- — 0.75% 1.50% 1.50% 1.50% 2.00% 4.50% 4.50%cyclodextrin HPMC 1.45% 1.40% 1.40% — 1.45% 1.40% 1.35% 1.40% CMC (%HPMC equivalent) — — — 1.40% — — — — PEG 400 — — — — — 0.25% — —Mannitol 2.50% 2.50% 2.50% 2.50% 2.50% 2.50% 2.50% 2.50% MgCl₂ 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% NaCl* 0.25% 0.25% 0.40% 0.30%0.25% 0.35% 0.40% 0.40% Citrate Buffer (mM) 3.00 3.00 3.00 3.00 3.003.00 3.00 3.00 pH 5.00 5.00 5.00 5.50 5.00 5.00 7.00 5.50 Menthol (mM)0.15 0.17 0.25 0.15 0.25 0.20 — 0.10 Sorbate — — — — 0.10% — — — (% w/v)139 140 141 142 143 144 145 Polysorbate 80 0.50% 0.50% 0.50% 0.50% 1.75%1.75% 3.5% Poloxamer 407 — — — — 0.75% 0.75% 0.1% Poloxamer 188 0.40%0.40% 0.40% 0.40% 1.25% 1.25% 0.1% Polyoxyl Castor oil 0.01% 0.01% 0.01%0.01% 0.01% 0.01% 0.01% Hydroxypropyl-gamma- 5.00% 5.00% 5.00% 5.00% — —— cyclodextrin HPMC 1.40% 1.45% — 1.40% 1.1% 1.1% 1.1% CMC (% HPMCequivalent) — — 1.40% — — — — PEG 400 — — — — 0.25% 0.25% 2.5% Mannitol2.50% 2.50% 2.50% 2.50% 0.75% 0.75% 1.0% MgCl₂ 0.10% 0.10% 0.10% 0.10%0.05% 0.05% 0.1% NaCl* 0.40% 0.40% 0.40% 0.40% 0.40% 0.40% 0.40% CitrateBuffer (mM) 3.00 3.00 3.00 3.00 4.00 4.00 4.00 pH 7.00 5.50 5.50 5.50 77 7 Menthol (mM) — 0.15 0.15 0.15 0.12 0.12 0.12 Sorbate — 0.10% — — —0.1% 0.1% (% w/v) 145B 145C 145D 145E 145F 145G 145H 145I Polysorbate 801.00% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer 407 0.50%0.50% 0.50% 0.50% 0.50% 0.50% 0.50% 0.50% Poloxamer 188 1.00% 1.00%1.00% 1.00% 1.00% 1.00% 1.00% 1.00% Polyoxyl Castor oil 0.01% 0.01%0.01% 0.01% 0.01% 0.01% 0.01% 0.01% HPMC 0.50% 0.50% 0.50% 0.50% 0.50%1.1% 1.1% 1.2% Mannitol 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25%PEG 400 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% MgCl₂ 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% NaCl* 0.30% 0.30% 0.30% 0.30%0.30% 0.30% 0.30% 0.30% Citrate Buffer (mM) 4.00 4.00 4.00 4.00 4.004.00 4.00 4.00 pH 7.00 7.00 7.00 7.00 7.00 7.00 7.00 7.00 Menthol (mM)0.06 0.09 0.09 0.12 0.15 0.09 0.09 0.09 Sorbate — — 0.10% — — — 0.10% —(% w/v) 145J 145K 145L 145M 145N 145O 145P Polysorbate 80 1.00% 1.00%1.00% 1.50% 1.50% 1.50% 1.00% Poloxamer 407 0.50% 0.50% 0.50% 0.70%0.70% 0.70% 1.00% Poloxamer 188 1.00% 1.00% 1.00% 1.00% 1.00% 1.00%0.20% Polyoxyl Castor oil 0.01% 0.75% 0.75% 0.25% 0.25% 0.25% 0.15%Hydroxypropyl-gamma- — — — — — — 1.50% cyclodextrin HPMC 1.2% 1.15%1.15% 1.10% 1.10% 1.10% 1.00% Mannitol 0.25% 1.75% 1.75% 2.50% 2.50%2.50% 1.00% PEG 400 0.25% 0.25% 0.25% — — — 0.50% MgCl₂ 0.10% 0.05%0.05% 0.10% 0.10% 0.10% 0.10% NaCl* 0.30% 0.25% 0.25% 0.25% 0.25% 0.25%0.35% Citrate Buffer (mM) 4.00 4.00 4.00 — — — 4.00 Phosphate Buffer(mM) — — — 3.00 3.00 3.00 — pH 7.00 7.00 7.00 5.7 5.7 5.7 5.7 Menthol(mM) 0.09 0.09 0.09 — 0.20 0.25 0.30 Sorbate 0.10% — 0.10% 0.10% 0.10%0.10% 0.11% (% w/v) 145Q 145R 145S 145T 145U 145V 145W Polysorbate 801.00% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer 407 1.00% 1.00%1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer 188 0.20% 0.20% 0.20% 0.20%0.20% 0.20% 0.20% Polyoxyl Castor oil 0.25% 0.25% 0.25% 0.25% 0.25%0.25% 0.30% Hydroxypropyl-gamma- 1.50% 1.50% 1.50% 1.50% 1.50% 1.50%1.50% cyclodextrin HPMC 1.20% 1.20% 1.20% 1.20% 1.20% 1.20% 1.20%Mannitol 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% PEG 400 0.50% 0.50%0.50% 0.50% 0.50% 0.50% 0.50% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%0.10% NaCl* 0.35% 0.35% 0.35% 0.35% 0.35% 0.35% 0.35% Phosphate Buffer(mM) 3.00 4.00 3.00 4.00 3.00 4.00 3.00 pH 5.7 5.7 6.0 6.0 6.2 6.2 6.2Menthol (mM) 0.27 0.27 0.27 0.27 0.27 0.27 0.27 Sorbate 0.10% 0.10%0.10% 0.10% 0.10% 0.10% 0.10% (% w/v) 145X 145Y 145Z 145AA 145AB 145AC145AD Polysorbate 80 1.50% 1.50% 1.50% 1.50% 1.50% 1.50% 1.50% Poloxamer407 0.70% 0.70% 0.70% 0.70% 0.70% 0.70% 0.70% Poloxamer 188 1.00% 1.00%1.00% 1.00% 1.00% 1.00% 1.00% Polyoxyl Castor oil 0.25% 0.25% 0.25%0.25% 0.25% 0.25% 0.30% Hydroxypropyl-gamma- 1.50% 1.50% 1.50% 1.50%1.50% 1.50% 1.50% cyclodextrin HPMC 1.20% 1.20% 1.20% 1.20% 1.20% 1.20%1.20% Mannitol 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% PEG 400 0.50%0.50% 0.50% 0.50% 0.50% 0.50% 0.50% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10%0.10% 0.10% NaCl* 0.35% 0.35% 0.35% 0.35% 0.35% 0.35% 0.35% PhosphateBuffer (mM) 3.00 4.00 3.00 4.00 3.00 4.00 4.00 pH 5.7 5.7 6.0 6.0 6.26.2 6.2 Menthol (mM) 0.27 0.27 0.27 0.27 0.27 0.27 0.27 Sorbate 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.11% (% w/v) 145AE 145AF 145AG 145AH145AI 145AJ 145AK Polysorbate 80 1.00% 1.00% 1.00% 1.00% 1.00% 1.00%1.00% Poloxamer 407 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer188 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% Polyoxyl Castor oil 0.25%0.25% 0.25% 0.25% 0.25% 0.01% 0.25% Hydroxypropyl-gamma- 1.50% 1.50%1.50% 2.50% 1.50% 1.50% 1.50% cyclodextrin HPMC — — 0.20% 1.00% 1.20%0.20% 0.70% Mannitol 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% PEG 4000.50% 0.50% 0.50% 1.00% 0.50% 0.50% 0.50% MgCl₂ 0.10% 0.10% 0.10% 0.10%0.10% 0.10% 0.10% NaCl* 0.35% 0.35% 0.35% 0.35% 0.35% 0.45% 0.45%Phosphate Buffer (mM) 4.00 4.00 4.00 4.00 3.00 — — Citrate Buffer (mM) —— — — — 3.00 3.00 pH 6.2 6.2 6.2 6.2 6.2 7.0 7.0 Menthol (mM) 0.15 0.250.01 0.37 0.01 0.10 0.27 Vitamin E (alpha-tocopherol) — — — — 129.1 — 10International units Sorbate 0.10% 0.10% 0.10% 0.10% 0.10% — 0.10% (%w/v) 145AL 145AM 145AN 145AO 145AP 145AQ 145AR Polysorbate 80 1.00%1.00% 1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer 407 1.00% 1.00% 1.00%1.00% 1.00% 1.00% 1.00% Poloxamer 188 0.20% 0.20% 0.20% 0.20% 0.20%0.20% 0.20% Polyoxyl Castor oil 0.25% 0.25% 0.01% 0.25% 0.25% 0.25%0.25% Hydroxypropyl-gamma- 1.50% 1.50% 1.50% 1.50% 1.50% 1.50% 1.50%cyclodextrin HPMC 0.85% 0.50% 0.20% 1.00% 1.20% 0.50% 1.10% Mannitol1.00% 0.75% 1.00% 1.00% 1.00% 0.75% 0.75% PEG 400 0.50% 0.50% 0.50%0.50% 0.50% 0.50% 0.50% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%NaCl* 0.45% 0.35% 0.40% 0.35% 0.35% 0.35% 0.35% Phosphate Buffer (mM) —— 3.00 4.00 4.00 4.00 4.00 Citrate Buffer (mM) 4.00 3.00 — — — 3.00 3.00pH 6.5 7.0 7.0 6.2 6.2 7.0 7.0 Menthol (mM) 0.32 0.32 0.01 0.27 0.270.30 0.30 Vitamin E (alpha-tocopherol) 15 35 — — — — — Internationalunits Sorbate 0.10% 0.10% — 0.10% 0.10% 0.10% 0.10% (% w/v) 145AS 145AT145AU 145AV 145AW 145AX 145AY Polysorbate 80 1.00% 1.00% 1.00% 1.00%1.00% 1.00% 1.00% Poloxamer 407 1.00% 1.00% 1.00% 1.00% 1.00% 1.00%1.00% Poloxamer 188 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% PolyoxylCastor oil 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25%Hydroxypropyl-gamma- 1.50% 1.50% 2.00% 2.00% 2.00% 2.00% 2.00%cyclodextrin HPMC 0.85% 0.50% — — — — — CMC — — 0.80% 0.80% 1.00% 1.10%1.20% Mannitol 1.00% 1.00% 0.75% 0.75% 0.75% 0.75% 0.75% PEG 400 0.50%0.50% 0.75% 0.75% 0.75% 0.75% 0.75% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10%0.10% 0.10% NaCl* 0.45% 0.45% 0.35% 0.35% 0.35% 0.35% 0.35% CitrateBuffer (mM) 4.00 4.00 4.00 4.00 4.00 4.00 4.00 pH 6.5 6.5 7.0 7.0 7.07.0 7.0 Menthol (mM) 0.32 0.36 0.38 0.32 0.32 0.32 0.32 Vitamin E(alpha-tocopherol) 15 35 30 — — — — International units Sorbate 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.10% (% w/v) 145AZ 145BA 145BB 145BC145BD Polysorbate 80 1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer 407 1.00%1.00% 1.00% 1.00% 1.00% Poloxamer 188 0.20% 0.20% 0.20% 0.20% 0.20%Polyoxyl Castor oil 0.25% 0.25% 0.25% 0.25% 0.25% Hydroxypropyl-gamma-2.00% 2.00% 2.00% 2.00% 2.00% cyclodextrin CMC 0.80% 1.40% 1.45% 1.40%1.45% Mannitol 0.75% 0.75% 0.75% 0.75% 0.75% PEG 400 0.75% 0.75% 0.75%0.75% 0.75% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% NaCl* 0.35% 0.35% 0.35%0.35% 0.35% Citrate Buffer (mM) 4.00 4.00 4.00 4.00 4.00 pH 7.0 7.0 7.07.0 7.0 Menthol (mM) 0.38 0.32 0.34 0.30 0.34 Vitamin E(alpha-tocopherol) 30 — — — — International units Sorbate 0.10% 0.10%0.10% 0.10% 0.11% *NaCl may be at a concentration from 0.1% to 0.75%,preferably from 0.2% to 0.5% “% HPMC equivalent” denotes an amount ofCMC necessary to result in a final viscosity equivalent to the finalviscosity achieved if the given % w/v of HPMC were used.

AQus™ Tears MGD may represent compositions of Table 7.

TABLE 7 AQus ™ Tears MGD Compositions (% w/v) 146 147 148 149 150 151152 153 Polysorbate 80 1.00% 1.00% 1.00% 1.00% 0.50% 0.50% 0.50% 1.00%Poloxamer 407 0.20% 0.20% 0.20% 0.20% — — — 0.50% Poloxamer 188 1.00%0.50% 0.50% 0.10% 0.10% 0.10% 0.10% 1.00% Polyoxyl Castor oil 0.01%0.50% 0.01% 1.00% 0.25% 0.25% 0.25% 0.50% Hydroxypropyl-gamma- 1.50%1.50% 1.50% 1.50% 3.00% 3.00% 3.50% — cyclodextrin HPMC 0.75% 1.25%0.65% — 1.35% — 1.35% 0.50% CMC (% HPMC equivalent) — — — 1.25% — 1.25%— 0.25% PEG 400 0.10% 0.50% 0.10% — — — — 0.25% Mannitol 2.50% 2.50%2.50% 2.50% 2.50% 2.50% 2.50% 0.10% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10%0.10% 0.10% 0.30% NaCl 0.40% 0.40% 0.50% 0.30% 0.40% 0.40% 0.40% 4.00Phosphate Buffer (mM) 3.00 3.00 3.00 3.00 3.00 3.00 3.00 — pH 7.00 7.007.00 7.00 7.00 7.00 7.00 7.00 Menthol (mM) 0.15 0.17 — — — — — 0.06Sorbate — — — — — — 0.10% — (% w/v) 154 155 156 157 158 159 160 161Polysorbate 80 1.00% 1.00% 1.00% 1.00% 1.50% 1.50% 1.50% 1.00% Poloxamer407 0.50% 0.50% 0.50% 0.50% 0.70% 0.70% 0.70% 1.00% Poloxamer 188 1.00%1.00% 1.00% 1.00% 1.00% 1.00% 1.00% 0.20% Polyoxyl Castor oil 0.50%0.50% 0.50% 0.50% 0.01% 0.01% 0.01% 0.15% HPMC 0.50% 0.50% 0.50% 1.35%1.30% 1.30% 1.30% 0.90% PEG 400 0.25% 0.25% 0.25% 0.25% — — — 0.50%Mannitol 0.25% 0.25% 0.25% 1.75% 2.50% 2.50% 2.50% 1.00% MgCl₂ 0.10%0.10% 0.10% 0.05% 0.10% 0.10% 0.10% 0.10% NaCl* 0.30% 0.30% 0.30% 0.25%0.35% 0.35% 0.35% 0.35% Citrate Buffer (mM) 4.00 4.00 4.00 4.00 — — — —Phosphate Buffer (mM) — — — — 3.00 3.00 3.00 4.00 pH 7.00 7.00 7.00 7.005.5 5.5 5.5 6.5 Menthol (mM) 0.09 0.12 0.15 0.09 — 0.20 0.25 0.30Sorbate — — — 0.10% 0.10% 0.10% 0.10% 0.11% (% w/v) 162 163 164 165 166167 Polysorbate 80 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer 4071.00% 1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer 188 0.20% 0.20% 0.20%0.20% 0.20% 0.20% Polyoxyl Castor oil 0.15% 0.15% 0.15% 0.15% 0.15%0.25% HPMC 0.90% 0.90% 1.00% 1.00% 1.00% 1.20% PEG 400 0.50% 0.50% 0.50%0.50% 0.50% 0.50% Mannitol 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% MgCl₂0.10% 0.10% 0.10% 0.10% 0.10% 0.10% NaCl* 0.35% 0.35% 0.35% 0.35% 0.35%0.35% Citrate Buffer (mM) — — — — — — Phosphate Buffer (mM) 3.00 3.004.00 4.00 3.00 4.00 pH 6.0 6.5 6.0 5.7 6.5 6.2 Menthol (mM) 0.25 0.250.25 0.25 0.25 0.27 Sorbate 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% d-alphatocopherol (IU) — — — — — 50 *NaCl may be at a concentration from 0.1%to 0.75%, preferably from 0.2% to 0.5% “% HPMC equivalent” denotes anamount of CMC necessary to result in a final viscosity equivalent to thefinal viscosity achieved if the given % w/v of HPMC were used.

TABLE 8 Additional AQus ™ Tears Compositions (% w/v) 168 169 170 171 172173 174 175 Polysorbate 80 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00%1.00% Poloxamer 407 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00%Poloxamer 188 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% PolyoxylCastor oil 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25%Hydroxypropyl-gamma- 2.00% 2.00% 2.00% 2.00% 2.00% 2.00% 2.00% 2.00%cyclodextrin CMC 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% PEG 4000.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% Mannitol 0.75% 0.75%0.75% 0.75% 0.75% 0.75% 0.75% 0.75% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10%0.10% 0.10% 0.10% NaCl 0.35% 0.35% 0.35% 0.35% 0.35% 0.35% 0.35% 0.90%Citrate Buffer (mM) 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 pH 7.0 7.07.0 7.0 7.0 7.0 7.0 6.0 Menthol (mM) 0.32 0.34 0.36 0.38 0.40 0.42 0.440.36 Sorbate 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% (% w/v) 176177 178 179 180 181 182 183 Polysorbate 80 1.00% 1.00% 1.00% 1.00% 1.00%1.00% 1.00% 1.00% Poloxamer 407 1.00% 1.00% 1.00% 1.00% 1.00% 1.00%1.00% 1.00% Poloxamer 188 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% 0.20%0.20% Polyoxyl Castor oil 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25%0.25% Hydroxypropyl-gamma- 2.00% 2.00% 2.00% 2.00% 2.00% 2.00% 2.00%2.00% cyclodextrin CMC 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40%PEG 400 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% Mannitol 0.75%0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% MgCl₂ 0.10% 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% NaCl 1.25% 1.50% 1.75% 1.50% 1.75% 2.00% 2.00%2.00% Citrate Buffer (mM) 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 pH 6.06.0 6.0 6.0 6.0 6.0 5.5 5.5 Menthol (mM) 0.36 0.36 0.36 0.38 0.38 0.380.38 0.40 Sorbate 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% (%w/v) 184 185 186 187 188 189 190 191 Polysorbate 80 1.00% 1.00% 1.00%1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer 407 1.00% 1.00% 1.00% 1.00%1.00% 1.00% 1.00% 1.00% Poloxamer 188 0.20% 0.20% 0.20% 0.20% 0.20%0.20% 0.20% 0.20% Polyoxyl Castor oil 0.25% 0.25% 0.25% 0.25% 0.25%0.25% 0.25% 0.25% Hydroxypropyl-gamma- 2.00% 2.00% 2.00% 2.00% 2.00%2.00% 2.00% 2.00% cyclodextrin CMC 1.40% 1.40% 1.40% 1.40% 1.40% 1.40%1.40% 1.40% PEG 400 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75%Mannitol 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% MgCl₂ 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% NaCl 0.35% 0.35% 0.35% 1.25%1.50% 2.00% 0.35% 1.50% Citrate Buffer (mM) 4.00 4.00 4.00 4.00 4.004.00 4.00 4.00 pH 7.0 7.0 7.0 6.0 6.0 5.5 7.0 6.0 Menthol (mM) 0.34 0.400.44 0.36 0.38 0.40 0.38 0.38 Sorbate 0.10% 0.10% 0.10% 0.10% 0.10%0.10% 0.10% 0.10% Camphor (mM) 0.1 0.1 0.1 0.1 0.1 0.1 — —Alpha-linolenic acid — — — — — — 0.1% 0.1% (% w/v) 192 193 194 195 196197 198 199 Polysorbate 80 1.00% 3.50% 3.50% 3.50% 1.00% 1.00% 1.00%1.00% Poloxamer 407 1.00% — — — — 1.00% 1.00% 1.00% Poloxamer 188 0.20%— — — — 0.20% 0.20% 0.20% Polyoxyl Castor oil 0.25% — — — — 0.25% 0.25%0.25% Hydroxypropyl-gamma- 2.00% — — — — 2.00% 2.00% 2.00% cyclodextrinCMC 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% PEG 400 0.75% 0.75%0.75% 0.75% 0.75% 0.75% 0.75% 0.75% Mannitol 0.75% 0.75% 0.75% 0.75%0.75% 0.75% 0.75% 0.75% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%0.10% NaCl 0.90% 0.90% 0.90% 0.90% 0.90% 0.90% 0.90% 0.90% CitrateBuffer (mM) 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 pH 6.00 6.00 6.00 6.00 6.006.00 6.00 6.00 Menthol (mM) 0.50 0.50 0.44 0.46 0.48 0.48 0.20 0.34Sorbate 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% (% w/v) 200 201 202 203204 205 206 207 Polysorbate 80 3.50% 3.50% 3.50% 3.50% 3.50% 3.50% 3.50%3.50% CMC 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% PEG 400 0.75%0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% Mannitol 0.75% 0.75% 0.75%0.75% 0.75% 0.75% 0.75% 0.75% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%0.10% 0.10% NaCl 0.90% 0.90% 0.90% 0.90% 0.90% 0.90% 0.90% 0.90% CitrateBuffer (mM) 4.0 5.0 4.0 4.0 4.0 4.0 4.0 4.0 pH 6.0 5.0 6.0 6.0 6.0 6.06.0 6.0 Menthol (mM) 0.5 — 1.2 2.0 4.0 0.75 0.4 0.2 Sorbate 0.1% 0.1%0.1% 0.1% 0.1% 0.1% 0.1% 0.1% (% w/v) 208 209 210 211 212 213 214 215Polysorbate 80 3.50% 3.50% 3.50% 3.50% 3.50% 3.50% 3.50% 3.50% CMC 1.40%1.40% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% PEG 400 0.75% 0.75% 0.75%0.75% 0.75% 0.75% 0.75% 0.75% Mannitol 0.75% 0.75% 0.75% 0.75% 0.75%0.75% 0.75% 0.75% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%NaCl — 0.90% 1.75% 1.25% 1.50% 1.75% 2.00% 2.00% Citrate Buffer (mM) 5.04.0 4.0 4.0 4.0 4.0 4.0 4.0 pH 5.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 Menthol(mM) — 1.0 0.75 2.0 4.0 1.75 0.4 0.2 Sorbate 0.1% 0.1% 0.1% 0.1% 0.1%0.1% 0.1% 0.1% (% w/v) 216 217 218 219 220 221 222 223 Polysorbate 80 —— — — 4.00% — — — Poloxamer 407 — — — — — 2.00% — — Poloxamer 188 — — —— — — 2.00% — Polyoxyl Castor oil — — — — — — — 2.00% CMC 1.40% 1.40%1.40% 1.40% 1.40% 1.40% 1.40% 1.40% Oleic Acid — 0.20% 0.20% 0.20% 0.20%0.20% 0.20% 0.20% PEG 400 — — 2.00% — — — — — PEG 20000 — — — 2.00% — —— — Mannitol — 2.00% 2.00% 2.00% 2.00% 2.00% 2.00% 2.00% MgCl₂ 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% NaCl 1.50% 1.50% 1.50% 1.50%1.50% 1.50% 1.50% 1.50% Zinc Sulfate — 0.10% 0.15% 0.20% 0.25% 0.25%0.25% 0.25% Citrate Buffer (mM) 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 pH 5.05.0 5.0 5.0 5.0 5.0 5.0 5.0 BAK 0.02% 0.02% 0.02% 0.02% 0.02% 0.02%0.02% 0.02% Sorbate 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% (% w/v) 224225 226 227 228 229 230 231 Polysorbate 80 — 1.00% 1.00% 1.00% 3.50%3.50% 3.50% 3.50% Poloxamer 407 — 1.00% 1.00% 1.00% — — — — Poloxamer188 — 1.00% 1.00% 1.00% — — — — Polyoxyl Castor oil — 1.00% 1.00% 1.00%— — — — Hydroxypropyl-gamma- 4.00% 1.00% 1.00% 1.00% — — — —cyclodextrin CMC 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% OleicAcid 0.20% 0.20% 0.20% 0.20% — — — — PEG 400 — — — 2.00% 0.75% 0.75%0.75% 0.75% PEG 20000 — — 2.00% — — — — — Mannitol 2.00% 2.00% 2.00%2.00% 0.75% 0.75% 0.75% 0.75% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%0.10% 0.10% NaCl 1.50% 1.50% 1.50% 1.50% 0.90% 0.90% 0.90% 0.90% Menthol(mM) — — — — 0.5 0.55 0.6 0.65 Zinc Sulfate 0.25% 0.25% 0.25% 0.25% — —— — Citrate Buffer (mM) 5.0 5.0 5.0 5.0 4.0 4.0 4.0 4.0 pH 5.0 5.0 5.05.0 6.0 6.0 6.0 6.0 BAK 0.02% 0.02% 0.02% 0.02% — — — — Sorbate 0.1%0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% (% w/v) 232 233 234 235 236 237 238239 Polysorbate 80 3.50% 3.50% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00%Poloxamer 407 — — 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer 188 — —0.20% 0.20% 0.20% 0.20% 0.20% 0.20% Polyoxyl Castor oil — — 0.25% 0.25%0.25% 0.25% 0.25% 0.25% CMC 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40%1.40% PEG 400 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% Mannitol0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% MgCl₂ 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% 0.10% NaCl 0.90% 0.90% 0.90% 0.90% 0.90% 0.90%0.90% 0.90% Menthol (mM) 0.7 0.75 0.5 0.6 0.65 0.7 0.85 1.0 CitrateBuffer (mM) 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 pH 6.0 6.0 6.0 6.0 6.0 6.06.0 6.0 Sorbate 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% (% w/v) 240 241242 243 244 245 246 247 Polysorbate 80 3.50% 3.50% — — — — — — Poloxamer407 — — 3.00% 3.00% 3.00% 3.00% 3.00% 3.00% CMC 1.40% 1.40% 1.40% 1.40%1.40% 1.40% 1.40% 1.45% PEG 400 0.75% 0.75% 0.75% 0.75% 0.75% 0.75%0.75% 0.75% Mannitol 0.75% 0.75% — — — — — 4.00% MgCl₂ 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% 0.10% NaCl 0.90% 1.25% — — — 0.25% 0.25% —Citrate Buffer (mM) 4.0 4.0 6.0 8.0 10.0 6.0 8.0 10.0 pH 6.0 6.0 5.0 5.05.0 5.0 5.0 5.0 Menthol (mM) 1.2 — — — — — — — Sorbate 0.1% 0.1% 0.1%0.1% 0.1% 0.1% 0.1% 0.1% (% w/v) 248 249 250 251 252 253 254 255Poloxamer 407 3.00% 3.00% 3.00% 3.00% 3.00% 3.00% 3.00% 3.00% CMC 1.45%1.45% 1.40% 1.45% 1.45% 1.45% — — Carbopol ® 940 — — — — — — 0.80% 1.00%PEG 400 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% Mannitol 4.00%4.00% 4.00% 4.00% 4.00% 4.00% 4.00% 4.00% MgCl₂ 0.10% 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% NaCl — 0.25% — 0.25% — 1.00% 1.00% 1.00% CitrateBuffer (mM) 8.0 8.0 8.0 8.0 8.0 8.0 8.0 8.0 pH 5.0 5.0 5.0 5.0 5.0 5.05.0 5.0 Menthol (mM) 0.4 0.4 0.4 0.4 0.8 0.8 0.8 0.4 Sorbate 0.1% 0.1%0.1% 0.1% 0.1% 0.1% 0.1% 0.1% (% w/v) 256 257 258 259 260 261 262 263Polysorbate 80 — — 3.50% 3.00% — 3.00% — — Poloxamer 407 3.00% 3.00% — —3.00% — 3.00% 3.00% CMC — — — 1.40% 1.40% 1.45% 1.45% — Carbopol ® 9401.20% 0.80% — — — — — 0.01% PEG 400 0.75% 0.75% 0.75% 0.75% 0.75% 0.75%— 0.01% PEG 20000 — — — — — — 0.75% — Mannitol 4.00% 4.00% 0.75% 1.50%1.50% 2.50% 2.50% 0.04% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%— NaCl 1.00% 1.00% 1.25% 0.25% 0.25% 0.50% 0.62% 0.01% Citrate Buffer(mM) 8.0 8.0 4.0 7.0 7.50 5.50 5.00 5.00 pH 5.0 5.0 6.00 5.0 5.0 5.0 5.05.0 Menthol (mM) 0.8 1.5 — — — 1.2 1.5 1.0 Sorbate 0.1% 0.1% 0.10% 0.10%0.10% 0.10% 0.10% (% w/v) 264 265 266 267 268 269 270 271 Polysorbate 80— — — 3.00% 3.00% — — — Poloxamer 407 3.00% 3.50% 3.00% — — 3.00% 3.00%3.00% CMC — — 1.40% 1.40% 1.45% 1.45% — — Carbopol ® 940 0.90% 1.20% — —— — 1.00% 1.00% PEG 400 0.01% 0.01% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75%Mannitol 0.03% 0.02% 1.50% 1.50% 4.00% 4.00% 4.00% 2.50% MgCl₂ — — 0.10%0.10% 0.10% 0.10% 0.10% 0.10% NaCl 0.01% 0.01% — — 0.75% 0.75% 0.75%0.65% Citrate Buffer (mM) 5.50 5.50 6.0 6.0 8.0 8.0 8.0 7.0 pH 5.0 5.05.0 5.0 5.0 5.0 5.0 5.0 Menthol (mM) 1.2 1.0 — — — — 1.0 1.0 Sorbate0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% (% w/v) 272 273 274 275 276 277278 279 Polysorbate 80 — 3.00% — 3.50% — — — — Poloxamer 407 3.00% —3.00% — 3.00% 3.50% 3.50% 3.50% Polyoxyl Castor oil 0.15% 0.15% 0.25%0.25% 0.25% 0.25% 0.25% 0.25% CMC — 1.40% 1.40% 1.45% 1.45% — — —Carbopol ® 940 1.00% — — — — 0.90% 1.10% 1.20% PEG 400 0.75% 0.75% 0.75%0.75% — 0.75% 0.75% — PEG 20000 — — — — 0.75% — 0.75% 0.75% Mannitol2.00% 1.50% 1.50% 2.50% 2.50% 4.00% 3.00% 2.00% MgCl₂ 0.10% 0.10% 0.10%0.10% 0.10% — — — NaCl 0.50% 0.25% 0.25% 0.50% 0.50% 0.25% 0.37% 0.50%EDTA 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% PVA — — 0.50% 0.50% 0.50%0.50% 0.50% 0.50% Citrate Buffer (mM) 6.0 7.0 7.5 5.5 5.0 5.5 5.5 5.5 pH5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Menthol (mM) 1.0 — — 1.2 1.5 1.0 1.51.75 Sorbate 0.1% 0.1% 0.1% 0.1% 0.1% 0.12% 0.12% 0.12% (% w/v) 280 281282 283 284 285 286 287 Polysorbate 80 — — — — — 1.00% 1.00% 1.00%Poloxamer 407 0.25% 3.50% 3.50% 3.50% 0.25% 1.00% 1.00% 1.00% Poloxamer188 0.20% 0.20% 0.20% Polyoxyl Castor oil 0.25% 0.25% 0.25% 0.25% 0.25%0.25% 0.25% 0.25% Sorbitol 3.00% — — — 1.75% — — — CMC — — — — — — —0.05% Carbopol ® 940 1.20% 0.90% 1.00% 1.20% 1.20% — — — PEG 400 — 0.75%0.75% 0.75% 0.75% — PEG 6000 — — — — — — — 0.75% PEG 20000 0.75% — 0.75%0.75% 0.75% — — — Mannitol 2.00% 1.00% 1.00% 1.00% 1.00% 0.75% 0.75%0.75% MgCl₂ — — — — — 0.10% 0.10% 0.10% NaCl 0.50% 0.75% 0.65% 0.70%0.45% 0.40% 0.40% 0.40% EDTA 0.1% 0.1% 0.1% 0.1% 0.1% — — — PVA 0.50%0.10% 0.10% 0.10% 0.10% — — — Citrate Buffer (mM) 5.5 4.0 4.0 4.0 4.02.5 2.5 2.5 pH 5.0 5.5 6.0 6.0 6.0 6.5 6.5 6.5 Menthol (mM) 1.75 0.401.00 1.25 1.75 — — — Sorbate 0.12% 0.12% 0.12% 0.12% 0.12% 0.12% 0.12%0.12% (% w/v) 288 289 290 291 292 293 294 295 Polysorbate 80 1.00% 1.00%1.00% 1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer 407 1.00% 1.00% 1.00%1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer 188 0.20% 0.20% 0.20% 0.20%0.20% 0.20% 0.20% 0.20% Polyoxyl Castor oil 0.25% 0.25% 0.25% 0.25%0.25% 0.25% 0.25% 0.25% Hydroxypropyl gamma — — — 1.00% 1.25% 1.50%1.75% 2.00% cyclodextrin CMC 0.05% 0.05% 0.10% 0.50% 0.75% 1.00% 1.10%1.20% PEG 400 — 0.75% 0.75% 0.75% 0.75% 0.75% — — PEG 6000 — — — — — —0.75% — PEG 20000 0.75% 0.75% — — — — — 0.75% Mannitol 0.75% 0.75% 0.75%0.75% 0.75% 0.75% 0.75% 0.75% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%0.10% 0.10% NaCl 0.40% 0.40% 0.60% 0.70% 0.75% 0.65% 0.85% 0.85% CitrateBuffer (mM) 2.5 2.5 3.0 3.5 4.0 4.5 5.0 5.5 pH 6.5 6.5 6.0 6.0 6.0 6.06.0 6.0 Menthol (mM) — — 0.10 0.15 0.20 0.25 0.30 0.40 Sorbate 0.12%0.12% 0.12% 0.12% 0.12% 0.12% 0.12% 0.12% (% w/v) 296 297 298 299 300301 302 303 Polysorbate 80 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00%1.00% Poloxamer 407 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00% 1.00%Poloxamer 188 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% PolyoxylCastor oil 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% Hydroxypropylgamma 0.60% 0.75% 0.75% 0.65% — — — — cyclodextrin CMC 1.30% 1.40% 1.50%1.60% — 0.1% 1.2% 1.2% PEG 400 0.75% 0.75% 0.75% 0.75% — — — — PEG 6000— 0.75% — — — 0.50% 0.50% 0.50% PEG 20000 0.75% 0.75% 0.75% 0.75% 0.75%— — — Mannitol 0.70% 0.75% 0.75% 0.75% 0.50% 0.50% 0.50% 0.50% MgCl₂0.10% 0.10% 0.10% 0.10% 0.07% 0.07% 0.07% 0.07% NaCl 0.60% 0.85% 0.85%0.85% — — — — Citrate Buffer (mM) 6.0 6.5 7.0 7.5 2.5 3.5 4.0 3.5 pH 6.05.5 5.5 5.0 6.5 6.0 6.0 5.5 Menthol (mM) 0.45 0.75 1.00 1.50 — 0.1 0.20.4 Sorbate — — — — — — — — (% w/v) 304 Polysorbate 80 1.00% Poloxamer407 1.00% Poloxamer 188 0.20% Polyoxyl Castor oil 0.25% Hydroxypropylgamma — cyclodextrin CMC 1.30% PEG 400 — PEG 6000 0.50% PEG 20000 —Mannitol 0.50% MgCl₂ 0.07% NaCl — Citrate Buffer (mM) 4.0 pH 5.5 Menthol(mM) 0.6 Sorbate —

In a preferred embodiment, artificial tear compositions of the presentinvention do not contain polyacrylates such as Pemulen® (Pemulen was aregistered trademark of B.F. Goodrich Company for polymeric emulsifiersand is now owned by and available from Lubrizol Advanced Materials,Inc.). Pemulen® materials including acrylate/C10-30 alkyl acrylatecross-polymers, or high molecular weight co-polymers of acrylic acid anda long chain alkyl methacrylate cross-linked with allyl ethers ofpentaerythritol.

In another embodiment, artificial tear compositions of the presentinvention do not contain boric acid, chlorobutanol, polyaminopropylbiguanide, or long chain fatty acids such as sesame oil (mixture oflinoleic acid, oleic acid, palmitic acid, and stearic acid) or flaxseedoil (mixture of linoleic acid, oleic acid, palmitic acid, stearic acidand alpha-linoleic acid).

Drug Vehicles

In one embodiment, all artificial tear compositions of the presentinvention are capable of being used as drug vehicle compositions.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   an active agent, preferably selected from the group consisting        of diquafosol, an antibiotic, a steroidal anti-inflammatory, a        nonsteroidal anti-inflammatory, a glaucoma drug, a        prostaglandin, a muscarinic receptor agonist, a miotic agent,        acetylsalicylic acid (“ASA”) and a combination thereof, more        preferably the active agent is selected from the group        consisting of diquafosol, bimatoprost, cyclosporine-A, GLC,        prednisolone forte, ketorolac, gentamycin, polytrim,        ciprofloxacin, moxifloxacin, gatifloxacin, lifitegrast,        besifloxacin, pilocarpine, brimonidine, timolol,        dexmedetomidine, timoptic, dorzolamide, latanoprost and a        combination thereof;    -   about 2.0% w/v polysorbate 80;    -   about 1.0% w/v poloxamer 188;    -   about 1.0% w/v hydroxypropyl-gamma-cyclodextrin;    -   about 1.35% w/v HPMC;    -   about 2.5% w/v mannitol;    -   about 0.10% w/v magnesium chloride;    -   about 0.30% w/v sodium chloride; and    -   about 3 millimolar citrate buffer, and an optional preservative        combination of one or more of:    -   about 0.005% to 0.02% BAK, 0.10% EDTA, and sorbate 0.10%.        wherein the composition has a pH of about 5.0. This latter        combination of preservatives and antioxidants has demonstrated        enhanced anterior chamber permeation, and duration to achieve        greater clinical benefit in some cases.

The present invention is further directed to A drug vehicle gelcomposition comprising:

-   -   an active agent;    -   one or more nonionic surfactants selected from the group        consisting of poloxamers, polysorbates, cyclodextrins, alkylaryl        polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and        polyoxyls at a total concentration from about 1.5% to about 5.9%        w/v; from about 0.5% to about 5% w/v hydroxypropylmethyl        cellulose (hypromellose) or an amount of a viscosity agent        selected from the group consisting of cellulose derivatives,        carbomers, gums, dextrans, polyvinyl alcohol, polyacrylic acids,        povidone, polyethylene glycol, propylene glycol, chitosans, and        hyaluronates and hyaluronic acids that yields a total viscosity        of the composition equal to the total viscosity of the        composition provided by from about 0.5% to about 5% w/v        hydroxypropylmethyl cellulose;    -   about 2.5% w/v mannitol;    -   about 0.10% w/v magnesium chloride;    -   from about 0.20% to about 0.30% w/v sodium chloride;    -   about 3 millimolar citrate or phosphate buffer; and    -   optionally, from about 0.07 millimolar to about 0.2 millimolar        menthol,        wherein the composition has a pH of at least 5.0.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   from about 0.05% to about 2.0% w/v cyclosporine-A, preferably,        from about 0.05% to about 0.09% w/v;    -   from about 1% to about 5% w/v of Captisol®, β-cyclodextrin or a        combination of Tween® β-cyclodextrin, preferably from about 3%        to about 4% w/v;    -   optionally, about 0.25% w/v polyoxyl 40 castor oil;    -   optionally, about 0.1% to about 1% w/v of an alcohol, preferably        from about 0.5% to about 1% w/v and preferably, the alcohol is        selected from the group consisting of a polyvinyl alcohol,        glycofurol, octoxynol 40 and a combination thereof;    -   optionally, from about 0.5% to about 1.25% hydroxypropylmethyl        cellulose or a concentration of carboxymethyl cellulose that        yields a total viscosity of the composition equal to the total        viscosity of the composition provided by from about 0.5% to        about 1.25% w/v hydroxypropylmethyl cellulose;    -   optionally, from about 0.1% to about 0.9% w/v sodium chloride,        preferably, about 0.3% w/v;    -   optionally, from about 0.5% to about 2.5% w/v mannitol;    -   optionally, about 0.1% magnesium chloride,    -   optionally, about 3 millimolar phosphate buffer or about 4        millimolar citrate buffer;    -   optionally, about 0.1% w/v sorbate; and    -   optionally, about 0.1 millimolar menthol,        wherein optionally, the composition has a pH of about 7.0.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   about 0.09% w/v cyclosporine-A;    -   about 3.0% to about 4.0% w/v poloxamer 407,    -   about 0.25% w/v sodium chloride;    -   about 0.2% or about 0.75% w/v hydroxypropylmethyl cellulose;    -   about 3 millimolar phosphate buffer or about 4 millimolar        citrate buffer;    -   optionally, about 1.0% w/v polysorbate 80;    -   optionally, about 0.01% w/v polyoxyl castor oil;    -   optionally, about 0.1% w/v sorbate;    -   optionally, about 0.1 millimolar menthol,        wherein the composition has a pH of about 7.0.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   from about 0.01% to about 2.0% w/v cyclosporine-A, preferably        from about 0.05% to about 0.09% w/v, more preferably about        0.05%, about 0.075% or about 0.09% w/v;    -   from about 1.0% to about 5.0% w/v polysorbate 80, preferably        from about 1.0% to about 4.0% w/v, more preferably from about        1.0% to about 1.5% w/v;    -   from about 0.1% to about 2.0% w/v poloxamer 407, preferably from        about 0.5% to about 0.7% w/v, more preferably about 0.5% or        about 0.7% w/v;    -   from about 0.1% to about 2.0% w/v poloxamer 188, preferably from        about 0.5% to about 1.5% w/v, more preferably about 1.0% w/v;    -   from about 0.001% to about 1.0% w/v polyoxyl castor oil,        preferably from about 0.005% to about 0.01% w/v, even more        preferably about 0.01% w/v;    -   from about 0.5% to about 4.0% w/v mannitol, preferably from        about 0.5% to about 3.0% w/v, more preferably from about 0.5% to        about 2.5% w/v;    -   from about 0.05% to about 0.1% w/v magnesium chloride, more        preferably about 0.05% w/v;    -   from about 0.1% to about 2.0% w/v hydroxypropylmethyl cellulose,        preferably from about 0.5% to about 1.35% w/v;    -   from about 0.1% to about 0.5% w/v polyethylene glycol 400        (“PEG-400”), preferably about 0.25% w/v;    -   from about 0.0% to about 0.9% w/v sodium chloride, preferably        from about 0.1% to about 0.40% w/v;    -   about 3 millimolar phosphate buffer or about 4 millimolar        citrate buffer;    -   from about 0.05% to about 2% w/v sorbate, preferably about 0.10%        w/v,    -   optionally, from about 0.07 to about 0.3 millimolar menthol; and    -   optionally, a preservative combination of one or more of:    -   about 0.005% to 0.02% BAK and 0.10% EDTA        wherein the composition has a pH of about 7.0.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   optionally, from about 3.0% to about 3.5% w/v diquafosol,        preferably about 3.0% or about 3.37% w/v;    -   from about 2.0% to about 6.0% w/v of one or more nonionic        surfactants, preferably the one or more nonionic surfactants is        selected from the group consisting of polysorbates, poloxamers,        polyoxyl castor oils, and cyclodextrins, more preferably        selected from the group consisting of polysorbate 80, poloxamer        407, poloxamer 188, polyoxyl castor oil and hydroxypropyl gamma        cyclodextrin;    -   from about 0.5% to about 0.75% w/v of a polyethylene glycol        having a molecular weight    -   from about 400 to about 20,000 Daltons;    -   from about 0.75% to about 3.0% w/v mannitol;    -   about 0.1% w/v magnesium chloride;    -   from about 1.1% to about 1.45% w/v carboxymethyl cellulose;    -   from about 0.4% to about 1.25% w/v sodium chloride;    -   about 3 millimolar phosphate buffer or from about 4 to about 5        millimolar citrate buffer;    -   from about 0.1% to about 0.12% w/v sorbate;    -   optionally, from about 0.1 to about 5.0 millimolar menthol,        preferably from about 0.2 to about 2.5 millimolar, more        preferably from about 0.2 to about 1.6 millimolar and most        preferably from about 0.1 to about 0.45 millimolar; and    -   optionally, about 2.0% w/v hydroxy-propyl-gamma-cyclodextrin,        wherein the composition has a pH from about 5.5 to about 7.0.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   about 3.0% w/v diquafosol;    -   about 3.00% w/v polysorbate 80;    -   about 0.75% w/v polyethylene glycol 400;    -   about 1.50% w/v mannitol;    -   about 0.1% w/v magnesium chloride;    -   about 1.40% w/v carboxymethyl cellulose;    -   about 0.90% w/v sodium chloride;    -   about 0.5 millimolar menthol;    -   about 4 millimolar citrate buffer;    -   about 1.0% w/v sorbate; and    -   about 2.0% w/v hydroxy-propyl-gamma cyclodextrin.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   optionally, from about 1.0% to about 1.5% w/v trehalose;    -   from about 2.0% to about 6.0% w/v of one or more nonionic        surfactants, preferably the one or more nonionic surfactants is        selected from the group consisting of polysorbates, poloxamers,        polyoxyl castor oils, and cyclodextrins, more preferably        selected from the group consisting of polysorbate 80, poloxamer        407, poloxamer 188, polyoxyl castor oil and hydroxypropyl gamma        cyclodextrin, preferably comprising about 1.00% w/v polysorbate        80, about 1.00% w/v poloxamer 407, about 0.20% w/v poloxamer 188        and about 0.25% w/v polyoxyl castor oil;    -   from about 0.50% to about 1.50% w/v of a polyethylene glycol        having a molecular weight of from about 400 to about 20,000        Daltons;    -   from about 0.50% to about 0.75% w/v mannitol;    -   from about 0.07% to about 0.10% w/v magnesium chloride;    -   from about 2.5 to about 6.0 millimolar citrate buffer;    -   optionally, from about 0.1% to about 1.30% w/v carboxymethyl        cellulose;    -   optionally, from about 0.4% to about 0.65% w/v sodium chloride;    -   optionally, from about 0.1 to about 0.45 millimolar menthol;    -   optionally, about 0.12% w/v sorbate,    -   wherein the composition has a pH from about 5.5 to about 6.5.

TABLE 9 Cyclosporine-A Drug Vehicles Formula #C1 #C2 #C3 #C4 #C5 #C6 #C7#C8 #C9 #C10 #C11 #C12 Cyclosporine- 0.05% 0.05% 0.05% 0.05% 0.075% 0.075%  0.075%  0.075%  0.09% 0.09% 0.09% 0.09% A Polysorbate  1.0% 1.5%  1.5%  1.5%  1.0%  1.5% 1.5% 1.5%  1.0%  1.5%  1.5%  1.5% 80Poloxamer  0.5%  0.5%  0.7%  0.7%  0.5%  0.5% 0.7% 0.7%  0.5%  0.5% 0.7%  0.7% 407 Poloxamer   1%   1%   1%   1%   1%   1%  1%  1%   1%  1%   1%   1% 188 Polyoxyl 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%  0.01% 0.01% 0.01% 0.01% Castor Oil HPMC 1.35% 1.35% 1.35% 1.35%1.35% 1.35% 1.35%  1.35%  1.35% 1.35% 1.35% 1.35% PEG-400 0.25% 0.25%0.25% 0.25% 0.25% 0.25% 0.25%  0.25%  0.25% 0.25% 0.25% 0.25% Mannitol1.75% 1.25%  2.5%  0.5% 1.75% 1.25% 1.5% 0.5% 1.75% 1.25%  1.5%  0.5%MgCl₂ 0.05% 0.05% 0.05% 0.05% 0.05% 0.05% 0.05%  0.05%  0.05% 0.05%0.05% 0.05% NaCl 0.25% 0.35% 0.25%  0.1% 0.25% 0.35% 0.4% 0.1% 0.25%0.35%  0.4%  0.1% Citrate Buffer 4 mM 4 mM 4 mM 4 mM 4 mM 4 mM 4 mM 4 mM4 mM 4 mM 4 mM 4 mM Sorbate  0.1%  0.1%  0.1%  0.1%  0.1%  0.1% 0.1%0.1%  0.1%  0.1%  0.1%  0.1% pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.07.0 7.0 Formula #C13 #C14 #C15 #C16 #C17 #C18 #C19 #C20 #C21Cyclosporine- 0.09% 0.05% 0.05%  0.09% 0.09% 0.05%  0.05% 0.05%  0.05% A Polysorbate  1.5%  1.5% 1.5%  1.5%  1.5% 1.5%  1.5% 1.75%  1.75%  80Poloxamer  0.7%  0.7% 0.7%  0.7%  0.7% — — — 0.7% 407 Poloxamer   1%  1%  1%   1%   1% — — 0.7% 1.0% 188 Polyoxyl 0.01% 0.01% 0.01%  0.01%0.01% 0.01%  1.25% 1.25%  1.25%  Castor Oil HPMC 1.35% 1.35% 1.35% 1.35% 1.35% 1.3%  1.3% 1.3% 1.3% Mannitol  2.5%  2.5% 2.5% 1.75% 1.75% —— — — MgCl₂  0.1%  0.1% 0.1% 0.05% 0.05% — — — — NaCl 0.25% 0.25% 0.25% 0.25% 0.25% 0.9% 0.75% 0.9% 0.9% Phosphate 3 mM 3 mM 3 mM — — 3 mM 3 mM3 mM 3 mM Buffer Sorbate — — 0.1% —  0.1% — — — — Glycerin — — — — —2.0%  2.0% 2.0% 2.0% pH 7.0 7.0 7.0 7.0 7.0 6.5 6.5 6.5 6.5

TABLE 10 Diquafosol Drug Vehicles Formula D1 D2 D3 D4 D5 D6 D7 D8Diquafosol — 3.00% — 3.00% — 3.00% — — Polysorbate 80 1.00% 1.00% 1.00%1.00% 1.00% 1.00% 3.00% 3.50% Poloxamer 407 1.00% 1.00% 1.00% 1.00%1.00% 1.00% — — Poloxamer 188 0.20% 0.20% 0.20% 0.20% 0.20% 0.20% — —Polyoxyl Castor Oil 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% — —Hydroxypropyl gamma 2.00% 2.00% — — 1.50% 1.50% 2.00% 2.00% cyclodextrinPEG-400 0.75% 0.75% 0.75% 0.75% 0.50% 0.50% 0.75% 0.75% Mannitol 0.75%0.75% 0.75% 0.75% 0.75% 0.75% 1.50% 3.00% MgCl₂ 0.10% 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% CMC 1.40% 1.40% 1.40% 1.40% 1.10% 1.10% 1.40%1.45% NaCl 0.90% 0.90% 0.90% 0.90% 0.40% 0.40% 0.90% 1.25% Menthol (mM)0.36 0.36 0.36 0.36 — — 0.5 1.0 Vehicle Diquas Diquas Diquas DiquasDiquas Diquas Diquas Diquas Citrate Buffer (mM) 4.0 4.0 4.0 4.0 — — 4.05.0 Phosphate Buffer (mM) — — — — 3.0 3.0 — — Sorbate 0.1% 0.1% 0.1%0.1% 0.1% 0.1% 0.1% 0.1% pH 6.00 6.00 6.00 6.00 7.00 7.00 5.5 5.5Formula D9 D10 D11 D12 D13 D14 D15 D16 Diquafosol 3.00% 3.00% — 3.00% —3.37% — 3.37% Polysorbate 80 3.00% 3.50% 1.00% 1.00% — — — — Poloxamer407 — — 1.00% 1.00% 3.50% 3.50% 3.50% 3.50% Poloxamer 188 — — 0.20%0.20% — — — — Polyoxyl Castor Oil — — 0.25% 0.25% 0.25% 0.25% 0.25%0.25% Hydroxypropyl gamma 2.00% 2.00% — — — — — — cyclodextrin PEG-4000.75% 0.75% 0.50% 0.50% — — — — PEG-6000 — — — — 0.75% 0.75% — —PEG-20000 — — — — — — 0.75% 0.75% Mannitol 1.50% 3.00% 0.75% 0.75% 0.75%0.75% 0.75% 0.75% MgCl₂ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%CMC 1.40% 1.45% 1.10% 1.10% 1.25% 1.25% 1.40% 1.40% NaCl 0.90% 1.25%0.90% 0.90% 0.90% 0.80% 0.90% 0.80% Menthol (mM) 0.5 1.0 0.60 0.60 — 0.8— 0.8 Vehicle Diquas Diquas Diquas Diquas Diquas Diquas Diquas DiquasCitrate Buffer (mM) 4.0 5.0 4.0 4.0 4.0 4.0 4.5 4.5 Phosphate Buffer(mM) — — — — — — — — Sorbate 0.1% 0.1% 0.1% 0.1% 0.12% 0.12% 0.12% 0.12%pH 5.5 5.5 7.0 7.0 6.0 6.0 6.0 5.5 Formula D10 Diquafosol 3.00%Polysorbate 80 3.50% Poloxamer 407 — Poloxamer 188 — Polyoxyl Castor Oil— Hydroxypropyl gamma — Cyclodextrin PEG-400 0.75% PEG-6000 — PEG-20000— Mannitol 0.75% MgCl₂ 0.10% CMC 1.40% NaCl — Menthol (mM) — VehicleDiquas Citrate Buffer (mM) 5.0 Phosphate Buffer (mM) — Sorbate 0.1% pH5.0

TABLE 11 Trehalose Drug Vehicles Formula T1 T2 T3 T4 T5 T6 T7 T8Trehalose 1.50% 1.50% 1.50% 1.00% — — — — Polysorbate 80 1.00% 1.00%1.00% 1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer 407 1.00% 1.00% 1.00%1.00% 1.00% 1.00% 1.00% 1.00% Poloxamer 188 0.20% 0.20% 0.20% 0.20%0.20% 0.20% 0.20% 0.20% Polyoxyl Castor Oil 0.25% 0.25% 0.25% 0.25%0.25% 0.25% 0.25% 0.25% Hydroxypropyl gamma — — 1.50% 0.60% — — — —cyclodextrin PEG-400 0.75% 0.75% 0.75% 0.75% — — — — PEG-6000 — — — —0.75% 0.50% — 0.50% PEG-20000 — — — 0.75% 0.75% — 0.75% — Mannitol 0.75%0.75% 0.75% 0.70% 0.50% 0.50% 0.50% 0.50% MgCl₂ 0.10% 0.10% 0.10% 0.10%0.07% 0.07% 0.07% 0.07% CMC — 0.10% 1.00% 1.30% — 0.10% — 1.20% NaCl0.40% 0.60% 0.65% 0.60% — — — — Menthol (mM) — 0.10 0.25 0.45 — 0.10 —0.20 Citrate Buffer (mM) 2.5 3.0 4.5 6.0 2.5 3.5 2.5 4.00 Sorbate 0.12%0.12% 0.12% — — — — — pH 6.5 6.0 6.0 6.0 6.5 6.5 6.5 6.0 Formula T9 T10Trehalose — — Polysorbate 80 1.00% 1.00% Poloxamer 407 1.00% 1.00%Poloxamer 188 0.20% 0.20% Polyoxyl Castor Oil 0.25% 0.25% Hydroxypropylgamma — — cyclodextrin PEG-400 — — PEG-6000 0.50% 0.50% PEG-20000 — —Mannitol 0.50% 0.50% MgCl₂ 0.10% 0.10% CMC 1.20% 1.30% NaCl — — Menthol(mM) 0.4 0.6 Citrate Buffer (mM) 3.5 4.0 Sorbate — — pH 5.5 5.5

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   from about 0.05% to about 0.09% w/v cyclosporine-A, preferably        0.05%, 0.075% or 0.09% w/v;    -   from about 1.0% to about 3.5% w/v polysorbate 80, preferably        1.5% or 3.5% w/v;    -   from about 0.5% to about 0.7% w/v poloxamer 407, preferably        about 0.7% w/v; about 1.0% w/v poloxamer 188;    -   from about 0.01% to about 0.75% polyoxyl castor oil, preferably        about 0.01% w/v polyoxyl castor oil;    -   from about 1.75% to about 2.5% w/v mannitol;    -   from about 0.05% to about 0.1% w/v magnesium chloride;    -   from about 0.5% to about 1.35% w/v hydroxypropylmethyl        cellulose, preferably from about 1.25% to about 1.35% w/v, more        preferably about 0.5%, 0.75%, 0.85%, 1.0%, 1.25% or 1.35% w/v;    -   about 0.25% w/v sodium chloride;    -   about 3 millimolar phosphate buffer or about 4 millimolar        citrate buffer;    -   optionally, from about 0.02 to about 0.09 millimolar menthol,        preferably about 0.02, 0.04, 0.06 or 0.09; and    -   optionally, a preservative combination of one or more of:    -   about 0.005% to 0.02% BAK, 0.10% EDTA, and sorbate 0.10%,        wherein the composition has a pH of about 7.0.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   from about 0.1 to about 1% w/v ketorolac tromethamine,        preferably 0.5% w/v;    -   from about 1.0 to about 3.5% w/v polysorbate 80, preferably 1.5%        or 3.5% w/v;    -   from about 0.5% to about 0.7% w/v poloxamer 407, preferably        about 0.7% w/v;    -   about 1.0% w/v poloxamer 188;    -   from about 0.01% to about 0.75% polyoxyl castor oil, preferably        about 0.01% w/v polyoxyl castor oil;    -   from about 1.75% to about 2.5% w/v mannitol;    -   from about 0.05% to about 0.1% w/v magnesium chloride;    -   from about 0.5% to about 1.35% w/v hydroxypropylmethyl        cellulose, preferably from about 1.25% to about 1.35% w/v, more        preferably about 0.5%, 0.75%, 0.85%, 1.0%, 1.25% or 1.35% w/v;    -   about 0.25% w/v sodium chloride;    -   about 3 millimolar phosphate buffer or about 4 millimolar        citrate buffer;    -   optionally, from about 0.02 to about 0.09 millimolar menthol,        preferably about 0.02, 0.04, 0.06 or 0.09; and    -   optionally, a preservative combination of one or more of:    -   about 0.005% to 0.02% BAK, 0.10% EDTA, and sorbate 0.10%,        wherein the composition has a pH of about 7.0.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   about 0.09% w/v cyclosporine-A;    -   about 3.5% w/v polysorbate 80;    -   about 0.25% w/v sodium chloride;    -   optionally, about 0.7% w/v poloxamer 407;    -   optionally, about 1.0% w/v poloxamer 188;    -   optionally, about 2.5% w/v mannitol;    -   optionally, about 0.5% w/v hydroxypropylmethyl cellulose;    -   about 3 millimolar phosphate buffer or about 4 millimolar        citrate buffer;    -   optionally, about 0.07 millimolar menthol; and    -   optionally, a preservative combination of one or more of:    -   about 0.005% to 0.02% BAK, 0.10% EDTA, and sorbate 0.10%,        wherein the composition has a pH of about 7.0.

In a preferred embodiment, the ratio of cyclosporine A to polyoxylcastor oil is greater than 0.08:1, more preferably from about 10:1 toabout 9:1, even more preferably from about 5:1 to about 9:1.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   about 0.06% w/v dexmedetomidine;    -   about 3.5% w/v polysorbate 80;    -   about 0.7% w/v poloxamer 407;    -   about 1.0% w/v poloxamer 188;    -   about 0.01% w/v polyoxyl castor oil;    -   about 2.5% w/v mannitol;    -   about 0.1% w/v magnesium chloride;    -   about 1.25% w/v hydroxypropylmethyl cellulose;    -   about 0.25% w/v sodium chloride; and    -   about 3 millimolar phosphate buffer,        wherein the composition has a pH of about 7.0.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   an effective amount of lifitegrast;    -   about 3.5% w/v polysorbate 80;    -   about 0.7% w/v poloxamer 407;    -   about 1.0% w/v poloxamer 188;    -   about 0.01% w/v polyoxyl castor oil;    -   from about 0.65% to about 1.25% w/v hydroxypropylmethyl        cellulose, preferably 0.65%, 0.85%, 1.0% or 1.25% w/v;    -   about 2.5% w/v mannitol;    -   about 0.1% w/v magnesium chloride; and    -   about 3 mM phosphate buffer;        wherein the composition has a pH of about 7.0.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   about 0.09% w/v cyclosporine-A;    -   about 4% w/v polysorbate 80; and    -   about 0.01% w/v polyoxyl castor oil.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   about 0.09% w/v cyclosporine-A;    -   about 3.5% w/v polysorbate 80;    -   about 4.0% w/v poloxamer 407; and    -   about 0.01% w/v polyoxyl castor oil.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   about 0.09% w/v cyclosporine-A; and    -   about 0.5% glycofurol.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   about 1.0% w/v ASA;    -   about 3.5% w/v polysorbate 80;    -   about 0.7% w/v poloxamer 407;    -   about 1.0% w/v poloxamer 188;    -   about 0.01% w/v polyoxyl castor oil;    -   about 2.5% w/v mannitol;    -   about 0.25% w/v sodium chloride;    -   about 0.1% w/v magnesium chloride;    -   about 1.25% w/v hydroxypropylmethyl cellulose;    -   about 3 millimolar phosphate buffer or about 4 millimolar        citrate buffer;    -   about 1.0% w/v polyethylene glycol 400; and    -   about 0.12% w/v sorbate,        wherein the composition has a pH of about 7.0 and wherein        optionally, the composition is for MGD or allergies.

The present invention is further directed to a drug vehicle compositioncomprising:

-   -   about 5.0% w/v ASA;    -   about 3.5% w/v polysorbate 80;    -   about 0.7% w/v poloxamer 407;    -   about 1.0% w/v poloxamer 188;    -   about 0.01% w/v polyoxyl castor oil;    -   about 2.5% w/v mannitol;    -   about 0.25% w/v sodium chloride;    -   about 0.1% w/v magnesium chloride;    -   about 1.25% w/v hydroxypropylmethyl cellulose;    -   about 3 millimolar phosphate buffer or about 4 millimolar        citrate buffer;    -   about 1.0% w/v polyethylene glycol 400; and    -   about 0.12% w/v sorbate,        wherein the composition has a pH of about 7.0 and wherein        optionally, the composition is for acne.

The present invention is further directed to a drug vehicle compositioncomprising from about 5.0% to about 10% w/v ASA in a composition of thepresent invention and optionally, from about 1% to about 10% w/v benzoylperoxide or octynol including octynol 11 or 309.

The present invention is further directed to a drug vehicle gelcomposition comprising:

-   -   an active agent, preferably selected from the group consisting        of diquafosol, an antibiotic, a steroid anti-inflammatory, a        nonsteroidal anti-inflammatory, a glaucoma drug, a        prostaglandin, a muscarinic receptor agonist, a miotic agent, an        antihistamine, acetylsalicylic acid and a combination thereof,        more preferably the active agent is selected from the group        consisting of diquafosol, KPI-121, lacritin, PRO-87, a        C-terminal 25 amino acid fragment of lacritin, tivanisiran,        omega 3 fatty acids, bimatoprost, cyclosporine-A, GLC,        prednisolone forte, ketorolac, gentamycin, polytrim,        ciprofloxacin, moxifloxacin, gatifloxacin, lifitegrast,        besifloxacin, pilocarpine, brimonidine, timolol,        dexmedetomidine, timoptic, dorzolamide, latanoprost and a        combination thereof;    -   one or more nonionic surfactants selected from the group        consisting of poloxamers, polysorbates, cyclodextrins, alkylaryl        polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and        polyoxyls at a total concentration from about 1.5% to about 5.9%        w/v, preferably about 2.0% w/v polysorbate 80, about 1.0% w/v        poloxamer 188 and about 1.0% w/v        hydroxypropyl-gamma-cyclodextrin;    -   from about 0.5% to about 20% w/v HPMC, preferably from about        0.5% to about 10% w/v and even more preferably from about 0.5%        to about 5.0% w/v;    -   about 2.5% w/v mannitol;    -   about 0.10% w/v magnesium chloride;    -   from about 0.2% about 0.30% w/v sodium chloride;    -   about 3 or 4 millimolar citrate or phosphate buffer; and    -   optionally one or more excipients selected from about 0.01% to        about 0.12% w/v sorbate, from about 0.01% to about 0.12% w/v        EDTA, and from about 0.005% to about 0.02% benzalkonium        chloride,        wherein the composition has a pH of about 5.0.

The present invention is further directed to a drug vehicle gelcomposition comprising from about 0.0075% to about 0.02% w/vbrimonidine, preferably from about 0.015% to about 0.02% w/v and one ormore nonionic surfactants selected from the group consisting ofpoloxamers, polysorbates, cyclodextrins, alkylaryl polyethers,polyoxyethyleneglycol alkyl ethers, tyloxapol, and polyoxyls at a totalconcentration from about 1.5% to about 5.9% w/v, preferably about 2.0%w/v polysorbate 80, about 1.0% w/v poloxamer 188 and about 1.0% w/vhydroxypropyl-gamma-cyclodextrin.

The present invention is further directed to a composition comprisingone or more nonionic surfactants and at least one excipient selectedfrom the group consisting of one or more viscosity enhancers, a polyoland an electrolyte, wherein micelles having an average diameter fromabout 12 to about 20 nanometers are formed, preferably from about 15 toabout 20 nanometers and more preferably about 16 nanometers.

The present invention is further directed to a composition comprising anactive agent selected from the group consisting of diquafosol,bimatoprost, cyclosporine-A, GLC, prednisolone forte, ketorolac,gentamycin, polytrim, ciprofloxacin, moxifloxacin, gatifloxacin,lifitegrast, besifloxacin, pilocarpine, brimonidine, timolol,dexmedetomidine, timoptic, dorzolamide, latanoprost, acetylsalicylicacid and a combination thereof, preferably cyclosporine-A, one or morenonionic surfactants and at least one excipient selected from the groupconsisting of one or more viscosity enhancers, a polyol and anelectrolyte, wherein micelles having an average diameter from about 12to about 20 nanometers are formed, preferably from about 15 to about 20nanometers and more preferably about 16 nanometers.

In a preferred embodiment, drug vehicle compositions of the presentinvention do not contain polyacrylates such as Pemulen® materialsincluding acrylate/C10-30 alkyl acrylate cross-polymers, or highmolecular weight co-polymers of acrylic acid and a long chain alkylmethacrylate cross-linked with allyl ethers of pentaerythritol.

Methods of the Invention

Conditions that may be treated by combining the micellar nonionicsurfactant discovered range for Moisture-Lock™ effect evaporative shield(from about 1.5% to about 5.5% w/v) are limited on the upper limit byincreased risk of epithelial toxicity. Within this critical range withvariations in viscosity, electrolytes, and preferred excipients allowsfor a wide range of characteristics appropriate for differentiatedtreatment opportunity. These treatment opportunities range from enhancedmoisture and contact lens deposit reduction and protection to moreeffective potential treatment of severe eye disease. Greater and moreprolonged exposure to natural tears that may be locked in by thediscoveries herein along with prolonged exposure to excipients found tobe protective to the corneal epithelium may enhance the currentlyinadequate treatments available for surface eye disease, particularlyrelated to corneal irritation and inadequate tear function and orvolume.

Autologous serum is often used to treat severe dry eye with greatereffectiveness than any other drug to date. Autologous serum consists ofspinning down blood and removing serum for topical application. Thisplasma is believed to contain many growth factors useful in optimizingtherapeutic benefit to the ocular surface and corneal epithelium inparticular. The sequestration of induced plasma triggered by thediscovered formulation properties of the present invention combined withthe trigger of the trigeminal nerve via TPV stimulation, of whichterpenoids are an example, provides a surrogate autologous serum withgreat potential therapeutic benefit. The induced plasma may bemaintained on the surface longer than autologous serum and is lesscostly and more practical to apply than autologous serum. Additionalbenefit derives from the combined discovery of tear sequestration andinduction of tearing consisting primarily of plasma is the creation of asurrogate autologous serum effect.

The present invention is further directed to a method of treating eyediscomfort comprising administering an artificial tear compositioncomprising:

-   -   1) from 0.2% to 7.0% w/v of at least one nonionic surfactant;        and    -   2) one or more non-Newtonian viscosity enhancing excipients of        high molecular weight blend having from about 0.1 centipoise        (cps) to about 3,000 cps @ 1% 27 C; to a subject in need        thereof.

The artificial tear compositions of the present invention are suitablefor administration two, three or four times per day to a subject in needthereof.

TABLE 10 Conditions to be Treated by Commercial Compositions ALL PRODUCTLINE AQus ™ CL-Tears AQus ™ Tears Plus AQus ™ Tears Advanced BASE:combines proprietary NIS 0.10% 0.50% 1.00% blend + V + electrolyte +epithelial protectants DEWS CLASSIFICATION I, II II+ III Visual blurDuration CONDITION: CL CL insertion coating protection CL pre, duringwear enhancement COMPUTER +, ++ ++, +++ +++, ++++ COSMETIC SHIELD +, ++++, +++ +++, ++++ ENVIRONMENTAL +, ++ ++, +++ +++, ++++ ALLERGIC +, ++++, +++ +++, ++++ PRESERVATIVE SHIELD +, ++ ++, +++ +++, ++++ DRY EYETHERAPY +, ++ ++, +++ +++, ++++ SPK THERAPY +, ++ ++, +++ +++, ++++ MGDTHERAPY +, ++ ++, +++ +++, ++++ GLAUCOMA DROP TOLERANCE +, ++ ++, ++++++, ++++ SURGERY — START: GLAUCOMA SURGERY — ++, +++ +++, ++++ LASIK —++, +++ +++, ++++ PRK — ++, +++ +++, ++++ CORNEAL TRANSPLANT — ++, ++++++, ++++ CATARACT SURGERY — ++, +++ +++, ++++ ALL PRODUCT LINE AQus ™Tears Advanced Plus AQus ™ Tears Extreme BASE: combines proprietary NIS1.35% VISCOSITY TO 350 blend + V + electrolyte + epithelial protectantsDEWS CLASSIFICATION III+, IV V Visual blur Duration CONDITION: CLCOMPUTER COSMETIC SHIELD ENVIRONMENTAL ALLERGIC ++++, +++++ PRESERVATIVESHIELD ++++, +++++ DRY EYE THERAPY ++++, +++++ +++++! SPK THERAPY ++++,+++++ +++++! MGD THERAPY ++++, +++++ +++++! GLAUCOMA DROP TOLERANCE++++, +++++ +++++! SURGERY GLAUCOMA SURGERY ++++, +++++ +++++! LASIK++++, +++++ +++++! PRK ++++, +++++ +++++! CORNEAL TRANSPLANT ++++, ++++++++++! CATARACT SURGERY ++++, +++++ +++++! Each + refers to diseasestatus: early (1), moderate (2), moderate-severe (3), severe (4),extreme (5 or 5!).

As seen in Table 10, varying the concentration of the viscosity enhancerand polyol provides different compositions that may serve differentpurposes. For example, a viscosity enhancer concentration of 0.10% w/vand polyol concentration of 1.00% w/v may be best suited for use on dryeye diseases classified as either a I or II by the international DEWSclassification system. Further, subjects with a disease that has reacheda severe state may benefit from a composition of the present inventioncomprising Captisol® or hydroxypropyl-gamma-cyclodextrin.

AQus™ CL-Tears may be used to treat mild dry eye and/or contact lensdryness. AQus™ CL-Tears is especially useful for the International DryEye Workshop (“DEWS”) classification I and II dry eye diseases. Further,AQus™ CL-Tears has an osmolarity less than about 320 osmoles and causesno visual blur upon instillation.

AQus™ Tears plus may be used to treat moderate dry eye. AQus™ CL-Tearsis especially useful for DEWS classification III dry eye diseases.Further, AQus™ CL-Tears has an osmolarity less than about 340 osmolesand causes about 5 seconds of visual blur upon instillation.

AQus™ Tears Advanced may be used to treat moderate to severe dry eye.AQus™ Tears Advanced is especially useful for DEWS classification IV dryeye diseases. Further, AQus™ Tears Advanced has an osmolarity less thanabout 360 osmoles and causes about 15-30 seconds of visual blur uponinstillation.

AQus™ Tears Advanced Plus and AQus™ Tears Extreme may be used to treatmoderate to severe dry eye. AQus™ Tears Advanced Plus and AQus™ TearsExtreme are especially useful for DEWS classification V dry eyediseases. Further, AQus™ Tears Advanced Plus and AQus™ Tears Extremehave an osmolarity greater than about 360 osmoles and causes about 30-60seconds of visual blur upon instillation.

AQus™ Tears MGD may be used to treat Meibomian Gland Dysfunction(“MGD”). AQus™ Tears MGD is especially useful for DEWS classificationI-IV dry eye diseases. Further, AQus™ Tears MGD has an osmolarity fromabout 300 to about 360 osmoles and causes about 10-15 seconds of visualblur upon instillation. Finally, AQus™ formulations noted to treat DEWSclassification III-IV dry eye diseases may also be used to treat MGD.

AQus is a trademark owned by PS Therapies, Ltd.

EXAMPLES Example 1-Moisture-Lock™ Effect as a Function of NonionicSurfactant Concentration

Moisture-Lock™ is defined by the Moisture-Lock™ Index. TheMoisture-Lock™ Index is calculated by multiplying the duration of thewetting effect in minutes by the qualitative wetness felt along the tearmenisci of the lower lids, rated from 0 to 4.0, maximum, for a specificduration of time sampled in equal increments. Alternatively, it can becalculated by multiplying the duration of the wetting effect by the tearprism in millimeters, which is coined Moisture-Lock™ Index 2. The valueof the qualitative method over the quantitative is the sensation ofmoisture. Moisture is the exact corollary to dryness from which 10million U.S. citizens alone are afflicted. In most cases of dry eyesyndrome, it is the sensation of dryness and related burning andirritation that are the most common debilitating symptoms. Additionalsymptoms include reduced contrast acuity, Snellen acuity, increasinglysevere discomfort and frank pain. The lower threshold for theMoisture-Lock™ Index that denotes Moisture-Lock™ effect is 10. Forexample, for a 40-minute duration sampled in 10-minute increments, aMoisture-Lock™ Index from 10 to 20 indicates slight Moisture-Lock™effect, from 21 to 75 indicates a moderate Moisture-Lock™ effect, from76 to 100 indicates a high Moisture-Lock™ and greater than 100 indicatesa very high Moisture-Lock™ effect. Shown below in Table 11 isMoisture-Lock™ Index for increments of total nonionic surfactant (“NIS”)concentration from 0.0% w/v to 7% w/v.

TABLE 11 Moisture-Lock ™ effect as a property of nonionic surfactantconcentration Wetness Rating NIS Duration (0 to 4.0; Moisture-Lock ™ (%w/v) (minutes) 4.0 maximum) Index Description 0% 1 1.5 1.5 10 0.5 5 20 00 30 0 0 40 0 0 Total 6.5 no ML 1% 1 2.0 2 10 1.5 15 20 0.5 10 30 0 0 400 0 Total 27 mod ML 3% 1 3.25 3.25 10 2.5 25 20 1.5 30 30 0.75 22.5 400.5 20 Total 100.75 high ML 5% 1 4 4 10 3.75 37.5 20 1.5 30 30 0.75 22.540 0.5 20 Total 114 very high ML 7% 1 3.5 3.5 10 3 30 20 1.25 25 30 0.515 40 0.25 10 Total 83.5 high ML “no ML” denotes no Moisture-Lock ™effect “mod ML” denotes moderate Moisture-Lock ™ effect “high ML”denotes high Moisture-Lock ™ effect “very high ML” denotes very highMoisture-Lock ™ effect “NIS” denotes nonionic surfactant

As can be seen in Table 11 and FIG. 1 the Moisture-Lock™ effect peaksaround 5.0% w/v total nonionic surfactant concentration with a normaldistribution as denoted by the bell-shaped curve in FIG. 1 . Further, ascan be seen in Table 11 and FIG. 2 use of about 5.0% w/v total nonionicsurfactant results in the greatest Moisture-Lock™ effect.

Example 2-Moisture-Lock™ Effect after Induced Tearing

The following experiment was conducted to test the enhancedMoisture-Lock™ effect of compositions of the present invention thatinduce tearing. The Moisture-Lock effect was measured as duration ofsensation of increased moisture and compared to a control artificialtear (Nanotears® XP). 2 drops of a composition of the present inventioncomprising polysorbate 1.5% w/v, poloxamer 407 0.20% w/v, poloxamer 1881.0% w/v, hydroxy propyl gamma cyclodextrin 1.0% w/v; mannitol 2.5% w/v;MgCl₂ 0.10% w/v; hydroxypropyl methyl cellulose 1.30% w/v, NaCl 0.45%w/v, citrate buffer 3 mM; and menthol 0.07 mM with a pH of 5.5(“composition S2-2”) was instilled in one eye of the first patient. 2drops of Nanotears® XP were instilled in one eye of a second patient.Moisture was quantified from 1-4 at 5-minute intervals from 5 to 50minutes. Results can be seen in Table 12 below.

TABLE 12 Sensation of Moisture following instillation of a compositionof the present invention Time (sec) Composition S2-2 Nanotears ® XP 5 44 10 4 3.5 15 3.5 2 20 2.75 1 25 2.5 0 30 2 — 35 1.5 — 40 1 — 45 0.5 —50 0 —

As demonstrated in Table 12, composition S2-2 maintained moisture for atleast twice as long as Nanotears® XP.

Example 3-Enhanced Comfort and Initial Instillation Qualities

Composition X:

3.00% Polysorbate 80 0.10% Poloxamer 188 0.01% Polyoxyl Castor oil 0.50%HPMC 2.50% Mannitol 0.10% MgCl₂ 0.75% NaCl 3 mM Phosphate buffer pH 7.00Method

One drop of Composition X was applied to the right eye and one drop ofRefresh Liquigel® applied to the left eye. After 30 minutes, aqualitative tear breakup time was calculated. A qualitative test wasconsidered more meaningful in terms of assessment of clinical benefitbecause observing and measuring quantity typically require addition of astain such as fluorescein. Further, the purpose of measuring the tearbreak up time is to assess when the tear film breaks up and dellenformation (dry spots) begin to form. This test was based on a) onset ofstinging and b) onset of reflex tearing vs. time without a blink. Visualblur following instillation was assessed as the time required to read4-point font at 40 cm that could be maintained for two blink cycles(initially blinking may cause viscous film resurfacing).

Results

Visual blur in the right eye lasted for fifteen seconds compared toninety seconds for the left eye. This six-times reduction in visual blurwas unexpected over the commercially available Refresh Liquigel®. Stingonset was delayed by four seconds over Refresh Liquigel® as CompositionX did not induce sting until twelve seconds after instillation ascompared to eight seconds for Refresh Liquigel®. Finally, reflex tearingonset was also delayed by four seconds over Refresh Liquigel® asComposition X did not induce reflex tearing until twenty seconds afterinstallation as compared to sixteen seconds for Refresh Liquigel®.

Example 4-(Hypothetical) Lid Wipes

Applications of preferred embodiments were applied to lid wipes,particularly compositions 86, 87, and 88 from Table 4 above. Preferablythe user first applied a warm pack or in some manner heated the lid wipeand then vigorously rubs along the lid margins in the region of themeibomian glands. Lid massage in the form of a rolled Q-Tip® followingthe vigorous lid wipe with compositions of the current invention may bebeneficial. The result is a greatly reduced incidence, if performedprophylactically, and a substantial therapeutic benefit to patients withMeibomian gland dysfunction (MGD). Dissolution of lipid deposits, withreduction in blocked lacrimal ducts, is augmented by this application ofthe present invention.

Example 5-Artificial Tear Gels

Artificial tear gels are virtually described for purposes of prolongedsurface contact with some added initial blur. These artificial tear gelsmay be used during a time that initial blur is unproblematic such asinsertion before sleep. Such gels may be with or without an active drugfor purposes of therapeutic treatment. An example of an artificial teargel of the present invention is described below with and without anactive ingredient.

Artificial Tear Gel

2.0% Polysorbate 80 1.0% Poloxamer 188 1.0% Hydroxypropyl gammacyclodextrin 1.5% to 20% Hydroxypropyl methyl cellulose (preferably 1.7%to 2.5%) 2.5% Mannitol 0.10% MgCl₂ 0.75% NaCl Citrate buffer to pH 5.00.10 mM Menthol

Lidocaine Tear Gel

1.0% Lidocaine 2.0% Polysorbate 80 1.0% Poloxamer 188 1.0% Hydroxypropylgamma cyclodextrin 1.5% to 20% Hydroxypropyl methyl cellulose(preferably 1.7% to 2.5%) 2.5% Mannitol 0.10% MgCl₂ 0.75% NaCl 3 mMPhosphate buffer pH 6.0

Cyclosporine-A Tear Gel

Cyclosporine-A 1.0% 2.0% Polysorbate 80 1.0% Poloxamer 188 1.0%Hydroxypropyl gamma cyclodextrin 1.5% to 20% Hydroxypropyl methylcellulose (preferably 1.7% to 2.5%) 2.5% Mannitol 0.10% MgCl₂ 0.75% NaClCitrate buffer to pH 5.0 0.15 mM Menthol

Advantages of these tear gel compositions are prolonged duration andminimized blur. The viscosity at low shear is from about 500 cps toabout 10,000 cps. Visual blur is less than 5 minutes. Maximummoisture-lock is precipitated.

Example 6-Night Vision Compositions (Virtual)

Compositions of the present invention may be used as a drug vehicle. Anexample of use as a drug vehicle is for pilocarpine for use as aninductor of miotic pupils. 0.075% w/v pilocarpine will be suspended insaline (0.9% w/v NaCl) and in a composition of the present inventiondetailed below. These two pilocarpine compositions will then beinstilled in the eye of a subject at separate times with a sufficientwash out period between instillations. Pupil size will be measured 1hour after instillation.

Pilocarpine Artificial Enhanced Tear

0.075% Pilocarpine 2.0% Polysorbate 80 1.0% Poloxamer 188 1.0%Hydroxypropyl gamma cyclodextrin 1.30% Hydroxypropyl methyl cellulose2.5% Mannitol 0.10% MgCl₂ 0.30% NaCl Phosphate buffer to pH 7.0Results

1 hour after instillation of pilocarpine in the artificial enhanced tearcomposition, the pupil size will be reduced by 1.5 mm vs 0.5 mmreduction in pupil size 1 hour after instillation of pilocarpine in thesaline composition.

Example 7-(Hypothetical) Cyclosporine-A Drug Vehicle

Cyclosporine-A is added to a composition of the present invention at aconcentration from about 0.05% to about 2.0% w/v, more preferably fromabout 0.075% to about 1.5% w/v, and most preferably from about 0.09% toabout 0.125% w/v. wherein the composition comprises one or more nonionicsurfactants are at a concentration from about 1.5% to about 4.9% w/v,more preferably from about 2.5% to about 4.0% w/v, a viscosity agent,preferably a cellulose derivative and most preferably HPMC or CMC at lowshear interblink viscosities of 50 cps to 500 cps, more preferably 100cps to 400 cps, optionally from about 0.01 to about 20 mM menthol,preferably from about 0.07 to about 12 mM and optionally a reduced pH,hypoosmolarity and or hyperosmolarity. The drug vehicle when combinedwith cyclosporine-A results in an enhanced duration and effectiveness ofthe anti-inflammatory effects of cyclosporine-A upon the secretory mucincells and other tear secretion glands of the lacrimal and accessorylacrimal apparatus. Further the drug vehicle enhances the generalanti-inflammatory effects of such compositions on the eye lid margins.

Example 8-Dexmedetomidine Drug Vehicle

2 drops of a composition comprising dexmedetomidine 0.075% w/v,polysorbate 4.0% w/v, hydroxypropylmethyl cellulose 1.35% w/v, sorbate0.10% w/v, BAK 0.02% w/v, EDTA 0.10% w/v, and a phosphate or a citratebuffer with a pH of 6.0 (“AQus™ Dex”) was in one eye of a first patientand 2 drops of a composition comprising dexmedetomidine 0.07% w/v insaline and phosphate buffer with a pH of 6.0 (“saline Dex”) wasinstilled in one eye of a second patient. Tests were performed tomeasure the intraocular pressure (“TOP”) in both eyes of each patient,where the non-instilled contralateral eye would thereby serve as ameasure of systemic absorption. The TOP was measured at baseline (1 pm),and drops were instilled subsequently at 8 am for check at 1 pm (5 hourspost instillation).

Results

Baseline TOP for both patients was 18.25 mm Hg. 5 hours afterinstillation of the saline Dex composition pressure in both eyes droppedto 13.5 mm Hg. In contrast, 5 hours after instillation of the AQus™ Dexcomposition pressure dropped to 12.0 mm Hg in the treated eye and 16.5mm Hg in the untreated eye.

These results demonstrate that the compositions of the present inventionare effective drug vehicles that reduce systemic absorption of theactive ingredient resulting in a more effective application with reducedsystemic side effects.

Example 9-Solubilization of Cyclosporine-A

Method

0.09% cyclosporine-A was added to several compositions in an attempt toprovide a stable, clear solution. Specifically, these compositions wereas follows: 1) 4% Captisol®, 2) 0.5% glycofurol, 3) 0.25% polyoxyl 35castor oil, 4) 4% γ-cyclodextrin, 5) 4% poloxamer 407, 6) 1% polysorbate80, 7) 4% Captisol® and 0.5% glycofurol, 8) 4% cyclodextrin, 0.5%glycofurol, and 0.25% polyoxyl 40 castor oil, 9) 4% poloxamer 188, 0.5%glycofurol and 0.02% BAK, 10) 2% polysorbate 80, 11) 3% polysorbate 80,12) 3.5% polysorbate 80, 13 4% polysorbate 80 and 0.01% polyoxyl castoroil and 14) 3.5% polysorbate 80, 4.0% poloxamer 407 and 0.01% polyoxylcastor oil.

Results

Compositions 1), 4-6), and 12) did not solubilize cyclosporine-A.Compositions 3), 10) and 11) sparingly solubilized cyclosporine-A.Compositions 7-9) resulted precipitate formation. Composition 12)solubilized cyclosporine-A but was not stable or clear. Compositions 2),13) and 14) solubilized cyclosporine-A and resulted in stable and clearsolutions.

Example 10-Increased Tear Volume with Cyclosporine-A Composition

Composition #C12 from Table 10, above, was instilled in each eye of asubject. Tear volume was calculated via the Schirmer's test at 5-minuteintervals to 45 minutes using phenol thread. After saline was used toclear the eyes of the subject, Restasis® was instilled in each eye ofthe same subject. Tear volume was calculated via the Schirmer's test at5-minute intervals to 45 minutes using phenol thread. Results from thisexperiment can be seen in FIG. 4 . Specifically, Composition #C12increased tear volume from 8.5 millimeters to about 10 millimeters at 15minutes after instillation, 15 millimeters at 20 minutes and peaked at20 millimeters at 30 minutes after instillation. After 30 minutes, thesubjects tear volume slowly decreased to 9.0 at 45 minutes. In contrast,installation of Restasis® in the eyes of the subject resulted in adecreased tear volume at all time points including a peak decrease toabout 6 millimeters at 15 and 30 minutes. Further, the subject reportedthat the lid margin felt only marginally wet 5 minutes afterinstillation of Restasis® and felt dry by 10 minutes after instillation.In contrast, the subject reported a welling of tears along the lidmargin at both 5 and 10 minutes after instillation of Composition #C12.The wet feeling continued through 20 minutes to marginally wet at 30minutes post instillation. The subject further reported minimal stingingwith Restasis® and no stinging with Composition #C12. Finally, theresubject reported only minimal blur lasting 15 seconds for each ofRestasis® and

Example 11-Nano-Micelle Size Distribution of Cyclosporine-A Compositions

Composition #C12 and Restasis® were each measured for nano-micelle sizedistribution. See FIG. 5 . As shown in FIG. 5 , the average diameter ofnano-micelles of Composition #C12 of the present invention was 16.3nanometers with a standard deviation of 5.55 nanometers. Restasis® hadan average size of 135.1 nanometers with a standard deviation of 77.81nanometers.

Example 12-Enhanced Tearing Using an all GRAS Artificial TearsComposition (Virtual)

Method

GRAS Composition—

2.0% w/v polysorbate 80 1.45% w/v carboxymethyl cellulose (high MW 2% =3,500 cps) 0.34 mM menthol 0.10% w/v sorbate Q.S. sterile saline 7.0 pH(adjusted)

A polyphenol thread (Zone Quick®) was used to provide a Schirmer'stesting measurement of tear volume. The thread was applied to thelateral canthus prior to administration of the formulation above andagain to the lateral canthus at time increments shown below. Theformulation was administered in to the right eye (“OD”) of the subjectand the left eyes of the subject (“OS”) was used as the control. Resultsof this experiment can be seen in Table 19 below.

Results

TABLE 13 Time OD OS (min) (mm) (mm) −1   9.5 9 5  30+ 8.5-9.5 10 228.5-9.5 15 17 8.5-9.5 30 17 8.5-9.5 45 12 8.5-9.5 60 12 8.5-9.5 75 108.5-9.5

The results of Table 13 indicate that the subject suffered from dry eyeprior to the instillation of the GRAS composition. Followinginstillation, the tear volume of the subjects treated eye increased forat least 1 hour.

Example 13-Effect of Sorbate Concentration on Tearing Production(Virtual)

Method

The dry eye subject of Example 12, above, was administered the GRAScomposition of Example 12, which includes 0.10% w/v sorbate; and twoadditional modified versions of the GRAS composition including a nosorbate composition and a 0.12% w/v sorbate composition.

Results

Tearing at 5-15 minutes:

Subject detected no difference between the 3 compositions in tearing at5 minutes post administration. However, subject noted enhanced tearingfor at least 10-15 minutes following administration with the 0.12% w/vsorbate composition along with a sharper sensation upon instillation.

What is claimed is:
 1. A drug vehicle composition consisting of: fromabout 0.05% to about 0.09% w/v cyclosporine-A; about 1.5% w/vpolysorbate 80; about 0.7% w/v poloxamer 407; about 1.0% w/v poloxamer188; about 0.01% w/v polyoxyl castor oil; from about 1.75% to about 2.5%w/v mannitol; from about 0.15% to about 0.25% w/v magnesium chloride;about 1.35% w/v hydroxypropylmethyl cellulose; about 0.25% w/v sodiumchloride; from about 0.1% to about 0.12% w/v sorbate; about 4 millimolarcitrate buffer; and water.
 2. The composition of claim 1, wherein thecomposition has a pH of about 7.0.